Agitation in Alzheimer's disease is a manifestation of frontal lobe dysfunction.

OBJECTIVES: (1) To investigate the prevalence and characteristics of agitation in patients with Alzheimer's disease (AD) and other forms of dementia; (2) to explore the association between agitation and other clinical variables, including disease severity, functional impairment and other neuropsychiatric symptoms, and (3) to determine the predictors of agitation. METHODS: Data for 427 men and women with dementia from outpatient clinics of the University of California, Los Angeles Alzheimer's Disease Center were analyzed. There were 277 patients with AD, 43 with vascular dementia, 47 with mixed dementia, 45 with frontotemporal dementia and 15 with dementia with Lewy bodies. Patients were evaluated with the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Functional Activities Questionnaire (FAQ), neuropsychological tests and the Caregiver Appraisal instrument. SPSS10 was utilized for statistical analysis. RESULTS: There was no difference in agitation subscale scores among patients with dementia of various etiologies. In patients with AD, there was increased prevalence of agitation with increasing dementia severity. Agitation contributed substantially to caregiver burden and impact. There was a significant correlation between the FAQ and the NPI agitation subscale score after adjusting for MMSE scores. Delusion, disinhibition and irritability subscale scores in AD patients were correlated with agitation across disease severity. Subscale scores of frontally mediated behaviors including irritability, delusions and disinhibition predicted most of the variance in agitation levels. CONCLUSION: Agitation is common in AD and other dementias and has a marked impact on caregivers. It is related to dementia severity and to specific types of associated psychopathology implicating frontal lobe dysfunction. The present study is the largest and most comprehensive assessment of agitation reported. The data suggest that agitation in AD is a frontal lobe syndrome. Frontal lobe dysfunction may predispose AD patients to agitation by exaggerating behavioral responses to many types of coexisting psychopathology or environmental provocations.

Comparison of pattern of breathing with other measures of induction of anaesthesia, using propofol, methohexital, and sevoflurane.

We assessed change of the pattern of breathing as a marker of induction of anaesthesia, using a method of maintaining spontaneous breathing throughout the induction period. We compared this index with a measure used clinically, the lash reflex, and measures used for drug investigations such as loss of grip of an object, cessation of finger tapping, and loss of arm tone. Ninety female patients (mean age 32 (17-63) yr, mean weight 63 (10) kg) were randomly allocated to induction of anaesthesia using propofol, methohexital, or sevoflurane. The i.v. agents were given by slow injection estimated to give an induction dose (for weight drop end point) in 90 s. Sevoflurane was given by progressively increasing the inhaled concentration to 8% so that induction should occur within 90-120 s. We measured time to change in breathing pattern, loss of voluntary finger tapping, loss of the lash reflex (tested at 15 s intervals), loss of postural tone in an outstretched arm, and loss of grip of a small metal cylinder held between finger and thumb. For methohexital and sevoflurane, the mean times for induction of anaesthesia occurred in the above order. With propofol, the lash reflex and tone were lost at the same time. The mean (SD) time to induction, by loss of arm tone was 64 (16) s for propofol, 83 (23) s for methohexital, and 94 (31) s for sevoflurane. The mean time to change in breathing pattern was 47 (20) s for propofol, 53 (14) s for methohexital, and 78 (29) s for sevoflurane. Although the time to achieve each end point was different, all the end points (except the lash reflex) appeared to provide similar measures of induction of anaesthesia. The pattern of breathing is an early sign of the onset of anaesthesia.

Neurobiology of cocaine-induced organic brain impairment: contributions from functional neuroimaging.

The present review is directed at imparting the current knowledge regarding functional neuroimaging as a tool for enhancing the understanding of cerebrophysiologic and neurobehavioral consequences of stimulant abuse. Stimulants like cocaine are capable of inducing clinically significant neurocognitive impairment through direct action on the brain, and indirectly through other organs that influence cerebral physiology. Neurochemical dysregulation including profound effects on the serotonergic and dopaminergic systems have substantial physiological and neurobehavioral consequences. Brain hemorrhages, transient ischemic attacks, strokes,and seizures frequently follow cocaine use. The residual cerebropathologic consequences of cocaine are seen only in significant or pronounced brain events when structural neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are employed. However, recent research with newer functional neuroimaging techniques such as single photon emission, positron emission tomography, and quantitative electroencephalography have revealed high rates of significant alteration in brain function among cocaine users, with negative structural imaging studies. These findings are often associated with impairment on neuropsychological evaluation, also in the absence of positive findings on CT and MRI. Both cerebral metabolic and hypoperfusion anomalies are seen, especially in anterior and temporal brain regions. Observed changes can persist for months, and for some patients, may represent a permanent change in brain functioning.

A review of the neuropsychological effects of commonly used prescription medications.

The practice of clinical neuropsychology has traditionally accorded limited attention to the impact of prescription medications on cognitive functioning. Though neuropsychologists see a wide array of patients with cerebropathologic and other organ system disease that are under pharmacotherapy, systematic attention to how these compounds potentially affect neuropsychological functioning has lagged. Psychomotor functioning, concentration, and memory are the most common cognitive domains negatively affected by such medications. In general sedative, psychomotor, and, to a lesser extent, attention/concentration effects covary and typically show tolerance with sustained drug administration. Memory effects are more resistant probably due to ongoing anticholinergic effects and the established link between the cholinergic system and memory functioning. This review covers the basic science and clinical literature addressing neuropsychological functioning both in healthy nonpatients and in patients treated with antidepressants, anxiolytics, stimulants, antihypertensives, antiepileptics and antihistamines. Critical to the understanding of the effects of these agents is the integration of multiple factors that modulate medication-induced neurocognitive effects, such as chronicity of treatment, tolerance, age, ethnicity, metabolic capacity, psychological, and neurological disorders in the patient, and the benefits of successful treatment of these disorders.

The pharmacologic treatment of anxiety and depression in African Americans. Considerations for the general practitioner.

A growing pool of recent research points to the importance of ethnicity in psychopharmacologic management of depression and anxiety disorders, with sometimes profound implications for efficacy and safety. Such research has provided provocative findings that illustrate important interethnic pharmacogenetic, pharmacokinetic, and pharmacodynamic differences, especially for African Americans. We did a systematic literature review of psychopharmacologic treatment considerations among African Americans with anxiety and mood disturbance seen by primary care physicians, who provide most psychopharmacologic treatment. The findings commonly point to a greater percentage of "poor metabolizers" among African Americans compared with Euro-Americans. General treatment considerations include greater attention to adverse effects and better clinical response and poorer compliance for a given dose, potential need for lower starting doses and slower increases, use of plasma drug levels if available, determination of past responses to a similar drug, and integration of pharmacogenetic information into an overall socioculturally and ethnically sensitive approach to assessment and treatment.

Cocaine-induced cerebrovascular impairment: challenges to neuropsychological assessment.

The patient who presents for evaluation and/or subsequent treatment of a neurological or psychiatric complaint accompanied by a positive history of substance abuse has generally received only modest attention in the clinical practice literature. Significantly more clinical attention has focused on the neurobehavioral sequelae of more pronounced brain insults, despite the rapid emergence of literature detailing psychopharmacologic-induced changes in brain-behavior functioning. This article describes recent clinical research findings related to the neuropsychology of cocaine use and associated issues of neurobiology and psychopharmacology. A description of strategies that have proven effective for assessing this population will be discussed. An emphasis on neurocognitive impairment that may precede as well as occur consequent to cocaine use are also examined. The literature reviewed here generally supports the conclusion that subgroups of cocaine abusing patients may demonstrate sustained brain perfusion anomalies and persistent neurocognitive deficits.

Comparison of lithium ratio between African-American and Caucasian bipolar patients.

Lithium RBC/plasma ratio (LR) was studied in 34 bipolar subjects on therapeutic doses of lithium carbonate. The sample was divided into 22 Caucasians and 12 African-Americans to observe possible ethnic differences in LR as previously reported. The latter group demonstrated a higher LR as well as increased reports of side effects (p < .05), even after controlling previous confounding factors. Our findings suggest that African-Americans may be more susceptible to the side effects associated with lithium treatment, and consequently, lower dosages may be necessary for this group.

Psychological characteristics related to cocaine use during pregnancy: a postpartum assessment.

This study assessed four psychological factors that have been suggested by previous research to be highly correlated with drug use. Twenty-one postpartum urban African-American women served as the research participants. At parturition, 10 infants tested positive for cocaine and 11 did not. Measures of depression (Beck Depression Index), anxiety (Spielberger Trait Anxiety Inventory), anger/self-control (Self-Analysis Questionnaire), and sociopathy (California Personality Inventory subscale) were obtained from the mothers within 6 weeks of delivery. Women who gave birth to cocaine-positive infants were significantly more depressed and had significantly higher sociopathy scores than their cocaine-negative counterparts. No differences with respect to anxiety and anger were obtained. The implications of these findings, as well as the potential adverse effects of cocaine use during pregnancy, are discussed.

Cerebral perfusion and neuropsychological consequences of chronic cocaine use.

Research indicates that cocaine significantly constricts the cerebral vasculature and can lead to ischemic brain infarction. Long-term effects of intermittent or casual cocaine use in patients without symptoms of stroke or transient ischemic attack were investigated. Single-photon emission computed tomography with xenon-133 and [99mTc]hexamethylpropyleneamine oxime, magnetic resonance imaging, and selected neuropsychological measures were used to study cerebral perfusion, brain morphology, and cognitive functioning. Patients were drug free for at least 6 months before evaluation. All showed regions of significant cerebral hypoperfusion in the frontal, periventricular, and/or temporal-parietal areas. Deficits in attention, concentration, new learning, visual and verbal memory, word production, and visuomotor integration were observed. This study indicates that long-term cocaine use may produce sustained brain perfusion deficits and persistent neuropsychological compromise in some subgroups of cocaine-abusing patients.

Pharmacokinetic and other related factors affecting psychotropic responses in Asians.

The last decade has witnessed substantial progress in our understanding of ethnic differences and similarities between Asians and other ethnic groups in response to various psychotropics. Capitalizing on recent advances in cross-cultural and psychobiological research methodology, a number of recent studies have suggested a special sensitivity of Asians to various psychotropic medications. Whereas pharmacokinetic differences have been consistently found with haloperidol and some benzodiazepines, results of studies focusing on tricyclic antidepressants (TCAs) have remained inconclusive. In addition, ethnic differences in protein binding and in the pharmacodynamics of some of these drugs have also been reported. Future studies should explore newer assay methods and imaging techniques capable of measuring receptor-drug interactions, in addition to utilizing existing research methodologies to more systematically scrutinize the nature and extent of such differences. They should be designed not only to ascertain differences in drug responses, but also to examine genetic and environmental (e.g., diet, exposure to enzyme inducers) factors that may contribute to these differences. Pharmacogenetic probes could be used in combination with studies examining pharmacokinetic and pharmacodynamic issues for such purposes.

Psychopharmacologic considerations in the treatment of black American populations.

Although striking ethnic differences in pharmacologic responses to various medications have been documented in the general medical literature, there is a paucity of such information in the psychopharmacologic literature. Recent work has provided a number of studies that illustrate interesting inter-ethnic pharmacogenetic, pharmacokinetic, and pharmacodynamic differences. In general, however, such studies have reported inconsistent findings relative to dose response relationships with various psychotropics. Results of our literature review, with a particular focus on black Americans, suggest that the lack of consistency in these investigations is largely attributable to various methodological and design problems. Prominent among these problems are: diagnostic misclassification, treatment of various ethnic groups in a homogeneous undifferentiated manner, lack of appropriate control for age and gender, and minimal consideration for chronicity of illness. As a result, though there exist some interesting data suggesting inter-ethnic genetic and kinetic differences, the extant literature on black Americans and other ethnic groups should be evaluated with some caution. The purpose of this article is to provide a systematic review of the existing psychopharmacologic literature on the black American population.

Ethnic psychopharmacology: the Hispanic and Native American perspective.

There is ample evidence attesting to differences in drug response and disposition among certain ethnic groups. The existing body of knowledge concerning pharmacological issues in the Hispanic and Native American ethnic groups, however, is both meager and confusing. In this article, the authors first attempt to briefly characterize these increasingly important ethnic groups, citing recent population figures and epidemiological findings. This is followed by a review of several existing retrospective studies concerning the pharmacological treatment of patients belonging to these groups. Recent findings in the area of pharmacogenetics are critically appraised and other factors influencing drug responsiveness are also examined. The clinical significance of this research for the optimal treatment of patients in cross-cultural settings is highlighted. The need for further research that would both fortify and clarify the available information with respect to these issues and the Hispanic and Native American populations is obvious.

Cardiovascular reactivity with caffeine and stress in black and white normotensive females.

Forty-eight healthy, young, normotensive black and white women, half with and half without a parental history of hypertension, were studied using a double-blind, randomized design. Systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) were recorded in response to 250 mg of caffeine vs placebo (3 mg) during rest and during a stressful mental arithmetic task. Results indicated no racial or parental history differences in response to caffeine or to stress. Surprisingly, our female subjects evidenced a small drop in SBP (1 mm Hg) and a decline in HR (5 bpm), and, as expected, they demonstrated a rise in DBP of 6 mm Hg in response to caffeine. The effects of caffeine on SBP and HR were contingent on the experimental condition such that the difference in SBP and HR between the high vs low dose of caffeine was significant only under the caffeine plus psychological stress condition. These effects were only partially consistent with those previously observed in males. Previous evidence of significantly greater DBP pressor effects when caffeine is consumed under stressful conditions was confirmed. However, in this study, the caffeine alone condition had little effect on SBP reactivity and promoted a decrease in HR reactivity. The results are discussed in relation to previous research on males, and recommendations for future research are offered.