Anticholinergic effects of medication in elderly patients.

Anticholinergic toxicity is a common problem in the elderly. It has many effects ranging from dry mouth, constipation, and visual impairments to confusion, delirium, and severe cognitive decline. The toxicity is often the result of the cumulative anticholinergic burden of multiple prescription medications and metabolites rather than of a single compound. The management of elderly patients, particularly those suffering from dementia, should therefore aim to reduce the use of medications with anticholinergic effects.

Risperidone for the treatment of behavioral and psychological symptoms of dementia.

Risperidone offers physicians the unique combination of extensive, published clinical experience and a good safety profile for treating patients with dementia who have symptoms of aggression, agitation, and psychosis. Numerous open-label and, more recently, placebo-controlled trials have documented the efficacy of risperidone in the management of behavioral and psychological symptoms of dementia. These trials also show that risperidone is better tolerated than conventional neuroleptic agents. Comparatively, patients treated with risperidone experience substantially fewer side effects, including extrapyramidal symptoms, cognitive toxicity, and tardive dyskinesia.

Assessing psychiatric illness in geriatric patients.

Assessing psychiatric illness in geriatric patients can be difficult for a variety of reasons. First, medical comorbidity may obscure the diagnosis. For example, the patient with multiple chronic illnesses will often have many "vegetative" symptoms of either dementia or depression (e.g., fatigue, loss of energy, poor appetite) attributed to the primary medical condition rather than to an underlying psychiatric illness. Second, the phenomenology of psychiatric illness in the elderly is often different. For example, depression in the elderly is often characterized by prominent anhedonia--loss of interest in virtually everything--and physical complaints leading to an unnecessary medical workup. Third, physicians are often reluctant to diagnose new-onset mental illness in their elderly patients. The fear of stigmatizing the patient or physician discomfort with "psychologic language" often results in underdetection of straightforward psychiatric syndromes. This article will focus primarily on detection of 3 of the most common psychiatric syndromes: dementia, depression, and delirium. The field of geriatric psychiatry has done a good job of characterizing the prevalence (Table I) and clinical features of these syndromes. The problem--briefly addressed here--is how to incorporate some of these findings into a busy clinical practice where there is very little time for the assessment of psychiatric symptoms.

Neuroleptic treatment of late-life schizophrenia.

There is a paucity of studies on the use of neuroleptic medication for treatment of the core symptoms of schizophrenia in elderly patients. The studies that are available have significant methodologic problems, including the mixing of early- and late-onset patients, inadequate outcome criteria, and the lack of control groups. Studies of conventional neuroleptics suggest that older patients have a moderate therapeutic response but are likely to develop side effects. The few studies of atypical antipsychotics now available suggest efficacy for treatment of behavioral disturbance in the elderly and a more favorable side-effect profile. The usefulness of all neuroleptics for the treatment of the core symptoms of late-life schizophrenia may depend on the duration and severity of the symptoms, with a poor response associated with greater severity and duration. It appears that patients with later-onset symptoms may respond better to all neuroleptics.

Serum anticholinergic activity levels and delirium in the elderly.

This article will briefly review the clinical studies focusing on measurement of serum levels of anticholinergic activity in delirious states. Three experimental approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current "list" includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigate the impact of anticholinergics on demented patients. Prevalence of delirium was significantly higher in patients receiving larger numbers of anticholinergics.

Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder.

OBJECTIVE: The authors used a functional neuroimaging study with a working memory probe to investigate the pathophysiology of attention deficit hyperactivity disorder (ADHD). Their goal was to compare regional cerebral blood flow (rCBF) changes related to working memory in adults with and without ADHD. METHOD: Using [(15)O]H(2)O positron emission tomography (PET) studies, the authors compared the sites of neural activation related to working memory in six adult men diagnosed with ADHD and six healthy men without ADHD who were matched in age and general intelligence. RESULTS: Task-related changes in rCBF in the men without ADHD were more prominent in the frontal and temporal regions, but rCBF changes in men with ADHD were more widespread and primarily located in the occipital regions. CONCLUSIONS: These data suggest the use of compensatory mental and neural strategies by subjects with ADHD in response to a disrupted ability to inhibit attention to nonrelevant stimuli and the use of internalized speech to guide behavior.

Acetylcholine and delirium.

The neurotransmitter acetylcholine has been implicated in animal and human studies of delirium. This chapter will briefly review the clinical studies focussing on measurement of serum levels of anticholinergic activity in delirious states. Three approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current 'list' includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigates the impact of anticholinergics on demented patients. Rates of delirium were significantly higher in patients receiving larger numbers of anticholinergics.

Depression and Alzheimer's disease.

Depressive symptoms, due either major depression or clinically significant, subsyndromal depression, occur commonly in the course of Alzheimer's disease. For a variety of clinical and methodological reasons, this remains an area that begs for new investigation. At the very least, these depressive symptoms should be viewed as a cause of significant and treatable "excess disability" (Kramer and Reifler, 1992). Demented patients with clinically significant depression (e.g., depressed mood, significant loss of appetite, insomnia, fatigue, irritability, and agitation) should be considered for a trial of antidepressant therapy, even when they fail to meet full diagnostic criteria for major depression. These symptoms will, in most instances, respond to antidepressant therapy. The "rules" for treatment of depression in dementia are slightly different than for cognitively intact patients: (a) start low, go slower, (b) pay attention to cognitive toxicity of all medication combinations, and (c) depressive symptoms do not persist as long as in cognitively intact patients. Current treatments, especially those SSRI's like fluoxetine and sertraline that have cognitive enhancing effects, should be considered the "first line" antidepressants. We need to emphasize early detection and treatment of depressive symptoms in dementia in all arenas.

New cholinergic therapies: treatment tools for the psychiatrist.

This article reviews the current status of therapy with acetylcholine-enhancing compounds in the management of patients with Alzheimer's disease. The focus is on pivotal articles investigating the role of cholinergic augmentation strategies, including precursor loading and acetylcholinesterase (AChE) inhibitors, in the management of cognitive and noncognitive symptoms of Alzheimer's disease. Precursor loading strategies have been for the most part unimpressive. By contrast, studies with AChE inhibitors--tacrine and donepezil--have been promising. For patients in whom hepatotoxicity and gastrointestinal side effects were not problematic, tacrine improves cognitive performance and selected secondary psychiatric symptoms and significantly delays nursing home placement. Donepezil, recently approved for use in mild to moderate Alzheimer's disease, appears to be less toxic and better tolerated than tacrine. It improves performance on cognitive testing and, in one preliminary investigation, demonstrated a sustained drug effect over several years. Therapy with AChE inhibitors provides modest significant symptomatic improvement in patients with mild to moderate Alzheimer's disease.

The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls.

BACKGROUND: There is evidence from animal and human experiments that learning and memory come under the separate influence of both cholinergic and serotonergic pathways. We were interested in learning whether serotonergic drugs could attenuate or exacerbate the memory-impairing effects of anticholinergic blockade in humans. METHODS: The selective serotonin 5-HT3 receptor antagonist ondansetron (0.15 mg/kg i.v.) and the serotonergic agent m-chlorophenylpiperazine (m-CPP; 0.08 mg/kg i.v.) were administered in combination with the anticholinergic agent scopolamine (0.4 mg PO) and compared to scopolamine alone in 10 young, healthy volunteers. Testing occurred on three separate days. RESULTS: As expected, i.v. administration of scopolamine induced significant impairments in episodic memory and processing speed; however, these scopolamine-induced cognitive deficits were not attenuated by pretreatment with i.v. ondansetron (0.15 mg/kg), nor were they exacerbated by administration of i.v. m-CPP (0.8 mg/kg) in addition to scopolamine; however, administration of i.v. m-CPP was followed by a significant increase of self-rated functional impairment, altered self-reality, and dysphoria ratings, and scopolamine's effect on pupil size was potentiated. CONCLUSIONS: Together, these results suggest that in young, healthy volunteers scopolamine-induced changes of cognitive performance are only minimally modulated by the serotonergic effects on ondansetron and m-CPP. Further studies with older controls are needed to test whether these findings may be influenced by age.

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness.

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer's disease compared to normal controls.

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups had smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.

Lack of relationship of neuroleptic dose and blood serum levels to neuropsychological performance on the LNNB in chronic schizophrenia.

The relationship of neuroleptic dose and blood serum levels to performance on the Luria Nebraska Neuropsychological Battery in chronic schizophrenics was assessed. Thirty chronic schizophrenics were individually administered the LNNB and a small sample of blood was obtained. No significant correlation between neuroleptic serum levels and test performance in these subjects was found although different conversion formulas related differentially to the blood serum levels.

Regional hypometabolism in Alzheimer's disease as measured by positron emission tomography after correction for effects of partial volume averaging.

Measurements of cerebral metabolism in patients with Alzheimer's disease (AD) using PET are artifactually depressed due to partial volume averaging of brain tissue activity with enlarged CSF spaces. To investigate the effects of correction for the expansion of CSF spaces on regional metabolic measures, as well as the correlations between neuropsychological test results and resting cerebral metabolism before and after partial volume correction, we applied an MRI-based method of partial volume correction to 18F-fluorodeoxyglucose (FDG)-PET data from eight patients diagnosed with probable AD and ten healthy elderly individuals. Before correction, the AD group had significantly lower cortex-to-cerebellum ratios in the posterior temporal, parietal, and frontal lobes in comparison to the control subjects. Partial volume correction of PET data resulted in 19 to 49% increases in regional activity in the AD group and 16 to 38% increases in the control group. The patients' persistence of significant hypometabolism in the frontal, posterior temporal, and parietal regions after partial volume correction suggests that a true reduction in regional cerebral glucose metabolism occurs in AD, even though its magnitude is a result of both metabolic reductions and the effects of atrophy. Partial volume correction of PET data in the AD group had a significant impact on the correlations between regional glucose metabolism and neuropsychological performance. These findings suggest that accounting for differential extent and distribution of cerebral atrophy in patients with AD and in healthy individuals may potentially improve our ability to interpret specific cognitive dysfunction in the context of the functional imaging data.

Striatal dopamine D2 receptor quantification and superior temporal gyrus: volume determination in 14 chronic schizophrenic subjects.

Chronic schizophrenic (n = 14) and normal subjects (n = 15) were studied with resonance imaging (MRI) and positron emission tomography (PET). Two PET scans were carried out to estimate caudate dopamine D2 receptor densities. MRI was used to measure the volume of the superior temporal gyrus. Average striatal D2 receptor density (Bmax) was significantly higher in the schizophrenic group than in the normal group. Average left superior temporal gyral volume was significantly smaller in the schizophrenic group than in the normal group, and the same tendency was found for the right superior temporal gyrus. Thus, the main finding of this combined analysis of functional and structural neuroimaging techniques was an inverse relationship between reduced superior temporal gyral volume and elevated striatal D2 receptor Bmax values. These preliminary findings require confirmation in larger groups of patients and control subjects.

Major depression in Alzheimer's disease. An interaction between gender and family history.

Major depression afflicts from 15% to 31% of patients with Alzheimer's disease (AD). The charts of 137 patients with AD were reviewed to assess the association between several variables and the risk of developing major depression. Thirty-eight patients (28%) had major depression. A family history of mood disorder was associated with a significantly increased risk for major depression, but this was only true in women (relative of odds = 2.82,95 confidence interval from 1.19 to 6.69). There was no relationship between major depression and a personal history of depression, younger age at onset of AD, history of substance use disorder, institutionalization, and marital status. These results suggest that the relationship between family history and depression in AD is more complex than previously thought.

Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans.

Cholinergic neurotransmission is thought to be modulated by serotonin as documented in animal and human studies. We examined the effects of the muscarinic antagonist scopolamine (0.4 mg IV) given alone or together with the serotonin mixed agonist/antagonist m-chlorophenylpiperazine (m-CPP, 0.08 mg/kg IV), and the selective 5-HT3 receptor antagonist ondansetron (0.15 mg/kg IV). Ten normal elderly volunteers each received five separate pharmacologic challenges (placebo, ondansetron, scopolamine, scopolamine+ondansetron, and scopolamine+m-CPP). Cognitive, behavioral, and physiologic variables were analyzed using repeated measures analysis of variance. The acute effects of scopolamine in certain cognitive, behavioral, and physiological measures were significantly exaggerated by the addition of m-CPP. Scopolamine's cognitive effects were unaffected by ondansetron at the dose tested, nor did ondansetron given alone affect basal cognitive performance. This pilot study suggests that the serotonin mixed agonist/antagonist m-CPP may influence cholinergic neurotransmission. The changes associated with the combination of scopolamine and m-CPP do not appear to be secondary to simple pharmacokinetic alterations and suggest a complex interaction between the cholinergic and serotonergic systems centrally.

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Changes in visual fixation and saccadic eye movements in Alzheimer's disease.

Visual fixation and saccadic eye movements were assessed in 31 mild to moderately demented patients with probable Alzheimer's disease (AD) and 31 age- and education-matched nondemented elderly control subjects. Seventeen AD and 17 matched control subjects were reassessed after a 9-month interval. On a fixation task, duration of fixation and number of intrusive saccades were not different between groups at baseline or follow-up. Both AD patients and control subjects showed more intrusive saccades at follow-up than at baseline. AD patients showed increased latency to initiation of saccades at baseline and on follow-up. Amplitude and velocity of saccades were not different between groups at any visit. Changes in measures of fixation, but no saccade measure, correlated with changes in MMSE scores over testing sessions. These data suggest that fixation is more sensitive than are saccades to the progession of AD.