Download Chapter 25 – Dementia

Chapter 25 – Dementia
Summary Points for the Primary Care Physician
•
Although most dementing illnesses are progressive, in some cases the course of the dementia may be modified
by appropriate therapeutic interventions.
•
Studies designed to define the reversibility of dementia have shown a minority of conditions in which the
cause of dementia was modifiable.
•
Complete clinical reversibility of dementia is possible, but not common, in routine clinical practice.
•
Depressed mood may be evident during the course of Alzheimer's disease in up to 50% of patients. About
10% to 20% meet criteria for major depression.
•
Frontotemporal dementias share several clinical features of Alzheimer's disease, such as progressive cognitive
deterioration and alterations in demeanor and behavior.
•
Dementia with Lewy bodies is characterized by marked fluctuation in cognition, visual and auditory
hallucinations, clouding of consciousness, and mild spontaneous extrapyramidal symptoms.
•
The incidence of vascular dementia is second to Alzheimer's disease as a cause of chronic progressive
intellectual decline.
•
Dementia syndrome of depression has been closely linked to subcortical cerebrovascular disease. Many of
these patients develop vascular dementia or Alzheimer's disease.
Practical Points for the Primary Care Physician
•
Apolipoprotein E (apo E) genetic testing is of limited value in the evaluation of late-onset Alzheimer's
disease, and is not routinely recommended.
•
Genetic testing of asymptomatic family members of patients with late-onset Alzheimer's disease has
inadequate predictive value for subsequent development of dementia and thus is not recommended.
•
Cholinesterase inhibitors are the standard treatment for persons with Alzheimer's disease; they have modest
efficacy in improving cognition, behavior, and function in those with mild to moderate dementia.
•
Memantine (combined with donepezil) is indicated for use in moderate to severe cases of Alzheimer's disease.
•
Although there is evidence demonstrating benefit of the use of atypical antipsychotics for elderly persons with
dementia and behavioral symptoms, there is also evidence that these medications may increase the risk of
cardiovascular adverse events, glucose intolerance, and death.
Dementia is a syndrome of acquired persistent dysfunction in several domains of intellectual ability, including memory,
language, visuospatial ability, praxis, gnosis, executive functioning, and calculation. Disturbances of mood and alterations
in demeanor often accompany the intellectual deterioration. Dementia results from a wide variety of conditions, including
degenerative, vascular, neoplastic, demyelinating, infectious, inflammatory, toxic, metabolic, and psychiatric disorders
( Table 25.1 ).[1] The onset of dementia may be abrupt (trauma or stroke) but is more often gradual. Although most
dementing illnesses are progressive, in some cases the course of dementia may be modified by appropriate therapeutic
interventions. Despite accurate identification of the cause of the dementia and provision of symptomatic treatment,
affected patients typically suffer marked and progressive impairment in occupational and social functioning. The
economic, social, and psychological cost of dementing illnesses on patients and their families is staggering. Dementia is a
growing public health concern across the world. Although exact figures vary, there is a consensus that the incidence and
prevalence of dementia increase with advancing age. In many studies, it has been reported that dementia affects almost
5% of the population over the age of 65 years. Dementia most frequently occurs in the fastest growing segment of the
population, those over age 75. Studies have suggested that 3% of the population between the ages of 65 and 74 may have
Alzheimer's disease (AD), the most common cause of dementia. This number increases to almost 19% of those aged 75 to
84 years and, among persons aged 85 years and older, may approach 50%.[2] It has been estimated that approximately 4.5
million Americans suffer from the disorder.[3] It is projected that within the next 50 years, between 11 and 16 million
persons will be afflicted in the United States. [4] [5] The disorder is reported to account for almost $1 billion in annual direct
and indirect expenses in the United States; long-term care of afflicted patients over the age of 65 has been estimated at
$40 billion annually.[4]
The anticipated expansion of the number of demented patients in the population and its associated cost raises serious
questions for those involved in health care planning. Issues to be resolved include choosing the most cost-effective
diagnostic tests for the routine evaluation of intellectual deterioration, selecting the most effective therapeutic and
management strategies, and planning the most humane and fiscally responsible type of long-term care.
This chapter reviews the clinical features of the major syndromes of dementia and discusses the essential components of
evaluation. Current guidelines for the treatment of the cognitive, functional, and behavioral consequences of dementia are
also discussed, with primary emphasis on Alzheimer's disease, the preeminent cause of dementia.
Table 25.1 -- Causes of dementia
Degenerative disorders
Cortical
Alzheimer's disease
Frontotemporal dementia, Pick's disease
Subcortical
Parkinson's disease
Progressive supranuclear palsy
Corticobasal ganglionic degeneration
Huntington's disease
Idiopathic basal ganglia calcification
Multisystem atrophy
Thalamic dementia
Dementia with Lewy bodies
Vascular dementias
Multiple large vessel occlusions
Lacunar state (multiple subcortical infarctions)
Binswanger's disease (hemispheric white matter ischemia)
Mixed cortical and subcortical infarctions
Metabolic disorders
Cardiopulmonary failure
Hepatic encephalopathy
Uremic encephalopathy
Anemia and hematologic conditions
Endocrine disturbances
Vitamin deficiency states
Porphyria
Toxic conditions
Medication toxicity
Alcoholic dementia
Polysubstance abuse
Heavy-metal intoxication
Myelin disorders
Normal-pressure hydrocephalus
Relative frequency of causes of
dementia
Neoplastic and paraneoplastic dementias
A classic study of the underlying
neuropathology in dementia was
Traumatic dementias
reported in 1968 by Blessed and
Infection-related dementias
colleagues.[6] The brains of 50
patients with chronic fatal dementia
Inflammatory disorders
who had died in an institution were
Psychiatric disorders
examined. Alzheimer's disease was
found in 50%, cerebrovascular
disease in 17%, and mixed AD and cerebrovascular disease in 25%. Together, neuropathologic changes consistent with
AD and cerebrovascular disease were found in more than 90% of all patients with dementia in this population.
Clinical studies analyzing the frequency of different illnesses in living patients with dementia have used various
assessment methodologies, patient selection criteria, and diagnostic approaches. In such studies, AD accounted for 39% to
70% of cases followed, in decreasing order of frequency, by vascular causes of cognitive impairment (13% to 37%) and
depression (1% to 18%). Various other conditions have been noted in 26% to 48% of cases. Dementing illnesses that are
potentially reversible but more often partially modifiable (including vitamin B12 and folate deficiency, hypothyroidism,
and depression) have been found in 3% to 29%. Dementias whose course could be influenced by appropriate therapeutic
interventions such as vascular disease or Parkinson's disease accounted for 20% to 46% of cases. [7] [8] [9]
As a group, these studies suggest that a host of disease states can cause or contribute to the development of dementia. In
some of these disorders, timely identification and subsequent treatment may alter the course of intellectual decline. In a
landmark study, Larson and coworkers[10] demonstrated that in a group of 200 patients over the age of 60 with suspected
dementia, over 30% had more than one medical condition that contributed to the dementia state. After treatment, 28%
experienced cognitive improvement for at least 1 month. In a related study, Farina and colleagues [11] reviewed a series of
513 patients referred to a memory clinic by their general practitioner to identify potentially reversible dementia. Of this
group of referred patients, 71% met criteria for dementia; 7% of these were deemed to have reversible causes. Of the
entire sample of demented patients, only 3.6% experienced “… a complete clinical and neuropsychological reversal of
dementia…” after treatment.[11] In 1.4% of those in the dementia sample, a partial regression of symptoms was noted. The
investigators noted that true reversibility of dementia, although not negligible, is rare in routine clinical practice. [11]
Lyketsos and associates[12] reported data from the population-based Cache County Study. This ongoing investigation is
focused on the epidemiology of dementia, the risk factors for conversion from predementia cognitive impairment to
dementia, and the progression of dementia. It was found that medical comorbidity was more serious in dementia patients
than in nondemented controls. Importantly, the seriousness of medical comorbidity in the demented patients was
significantly associated with worse daily functioning and cognition. The need for further investigation into the
consequences of treatment of medical comorbidity on dementia progression was emphasized.[12]
Major syndromes of dementia
Alzheimer's disease
Alzheimer's disease is the most common cause of dementia in the elderly. The onset of the disease is insidious, generally
occurring after the age of 55 years and increasing in incidence with advancing age. The average risk of developing AD is
approximately 5% at age 65 years, and subsequently increasing twofold every 5 years.[13] The clinical course is marked by
a gradual deterioration of intellectual function, a decline in the ability to accomplish routine activities of daily living, and
enduring changes in personality and behavior. Useful guidelines for the clinical diagnosis of Alzheimer's disease were
established by McKhann and coworkers. These have now been applied for more than 2 decades, during which clinical
sophistication in the approach to diagnosis has matured.[14] These criteria require that the patient be between the ages of 40
and 90 years at the time of disease onset, demonstrate progressive loss of memory, and have impairment of at least one
additional neuropsychological function. These required deficits must be documented by a standardized mental status
examination and neuropsychological assessment. Finally, no additional systemic or brain disorder may be present that
could be the cause of the dementia.
The neurobehavioral features of classic dementia of the Alzheimer type include memory impairment, executive
dysfunction, disturbances in language (aphasia), visuospatial deficits, and impaired ability in calculation and abstraction.
Disturbances of other cortical functions such as agnosia (impaired recognition) and apraxia (inability to carry out a motor
task in the absence of sensory loss, hemiparesis, or difficulty in comprehension) may be observed. The memory
impairment characteristic of AD includes deficits in new learning and an inability to recall previously learned material
accurately. Patients are noted to be markedly forgetful and repetitive; there is a tendency to misplace items. Executive
dysfunction is marked by difficulties in organization, planning, and strategizing. The language disturbance typical of AD
is best characterized as a transcortical sensory aphasia—there is a fluent verbal output accompanied by anomia, impaired
auditory comprehension, preserved repetition, and aphasic writing. Although patients may be able to read aloud, their
comprehension for written material is impaired.[15] To the casual listener, affected patients have difficulty finding words
and may inappropriately substitute related words or improper phonemes when conversing. The patient's verbal discourse
is vague to the listener and lacks clear direction of purpose (circumlocution). In group discussions, as a consequence of
impaired auditory comprehension, the patient is often noted to be uncharacteristically passive and remote.
Visuospatial impairment is evidenced by environmental disorientation and an inability to draw figures or copy designs.
Patients so affected have difficulty navigating and may get lost traveling to familiar places.
Alterations in demeanor are an early and ubiquitous finding in AD. Commonly, patients become increasingly passive, are
more coarse in their display of emotions, and are less spontaneous. Some of these symptoms may mimic those of
depression, but more often they occur in the absence of a clearly depressed mood or with thoughts of worthlessness,
hopelessness, or guilt. Depressed mood may be evident at some time during the course of the illness in 40% to 50% of
patients. However, the percentage of patients with AD who meet strict diagostic criteria for major depression is
considerably lower (10% to 20%).[16] In up to 50% of patients with AD, psychosis with delusions of infidelity, theft, harm,
or abandonment is encountered.[17] These symptoms usually evolve as the severity of the dementia progresses.
Hallucinations may also occur in patients with AD, but are less common than delusions. When they do occur, an
aggressive search for comorbid causes of delirium should be commenced. Such phenomena may be visual and auditory in
nature. Other behavioral abnormalities frequently encountered in AD include motor restlessness, verbal or physical
agitation, resistiveness, anxiety, catastrophic reactions, aggressivity, purposeless wandering, hoarding, and insomnia.[18]
Although patients with AD present with striking neuropsychological and behavioral disturbances, primary motor,
somatosensory, and visual functions remain intact throughout most of the disease course. In classic AD, extrapyramidal
dysfunction (e.g., parkinsonism, tremor, chorea) is absent, and neurologic abnormalities such as rigidity, myoclonus,
ataxia, seizures, and dysarthria do not appear until the late stages.
In the middle stage of AD, electroencephalography (EEG) may show theta-range slowing. Structural neuroimaging
studies such as computed tomography (CT) or magnetic resonance imaging (MRI) are normal or show mild cerebral
atrophy. In later stages, EEG may show delta-range slowing and CT or MRI disclose moderate to severe degrees of
cortical and central atrophy, as evidenced by sulcal enlargement and ventricular dilation. Nonspecific age-related ischemic
changes are also frequently reported. Although invariably present, these findings are not specific to AD. More recently,
functional neuroimaging techniques have been applied to the diagnostic evaluation of AD. In single-photon emission
computed tomography (SPECT), the classic AD pattern is reported to be bilateral reduced cerebral blood flow to the
posterior parieto-occipitotemporal junctions. In positron emission tomography (PET), the characteristic abnormality of
AD is reduced glucose metabolism in these same brain regions. Frontal hypoperfusion in SPECT and hypometabolism in
PET are also invariably present.
The clinical features of AD reflect the relatively selective involvement of parietal, medial temporal, frontal convex, and
basal forebrain regions found at autopsy. The neuropathologic alterations characteristic of AD include neuronal loss,
gliosis, an abundance of neuritic plaques, neurofibrillary tangles, amyloid angiopathy, and granulovacuolar
degeneration.[19] Neurochemical abnormalities in AD include cholinergic depletion, excessive synaptic glutamate, and
more variable disturbances of the noradrenergic and serotonergic systems.
Risk factors for AD have been reported to include age, female gender, head trauma, family history of AD, Down
syndrome, low educational level, and the presence of the apolipoprotein epsilon 4 (apo E4) allele on chromosome 19.
Additional risk factors for the development of AD have been identified; these include elevated serum homocysteine levels,
hypertension, and hypercholesterolemia. Protective factors that have been noted in epidemiologic studies and are under
active investigation as preventive strategies include the statin class of cholesterol-lowering agents[22] and nonsteroidal
anti-inflammatory drugs (NSAIDs).[23] For some time, it was thought that estrogen use might offer protective effects
against the development of AD.[24] However, the Women's Health Initiative Memory Study later found that estrogen alone
or in combination with progestin may actually increase the risk of dementia. [25] [26]
The extent to which AD is an inherited disease has not yet been fully elucidated. Generally, about 50% of all cases of AD
are thought to reflect genetic influences directly. Several important advances have identified three separate chromosomal
loci as causal factors for early-onset familial AD—the presenilin genes 1 (chromosome 14) and 2 (chromosome 1) and the
amyloid precursor protein (APP) gene (chromosome 21). Mutations in these genes appear to be most frequently associated
with the familial onset of AD before the age of 60 years. In the presence of mutations in these genes, AD appears to be
inherited in an autosomal dominant fashion, with full penetrance. The apo E4 allele has been reported to be a significant
genetic risk or susceptibility factor for AD. Although not causative, this allele is more common in those who develop
sporadic or late-onset familial AD. Although only 15% of the general population has an apo E4 allele, 40% of patients
with AD possess this risk factor. The number of apo E4 alleles correlates with an earlier age of onset as well as with an
increased risk for development of the disease.[27] Additional genetic risk factors under investigation for late-onset (familial
and nonfamilial) AD are cytochrome P450 (CYP) 46-TT polymorphism, α2-macroglobulin, insulin-degrading enzyme,
and the ubiquilin 1 gene.
Frontotemporal dementia
Pick's disease, or Pick's complex, and other frontotemporal dementias (FTDs) are a heterogeneous group of disorders that
share several clinical features with AD, such as progressive cognitive deterioration and alterations in demeanor and
behavior. Many FTD patients are also aphasic and manifest preserved motor integrity. The language disturbance of these
disorders initially includes anomia, with a more stereotyped and perseverative verbal output than that found in AD. In the
early stages of FTD, unlike AD, memory, calculation, and visuospatial function are relatively well preserved. The most
striking feature of this disorder is an extravagant change in the patient's demeanor, including disinhibition, impulsivity,
inappropriate jocularity, and intrusiveness. In some patients, the behavioral changes consist of especially prominent
passivity or atypical depressive symptoms; there may be elements of the Kluver-Bucy syndrome (e.g., hyperorality,
dietary changes, compulsive exploratory behaviors, hypersexuality, agnosia, and placidity).[28] Motor neuron disease has
also been associated with FTD, and has a more rapidly progressive course than the other types. In FTD, EEG may show
diffuse or frontal-temporal slowing. CT or MRI frequently reveal focal frontal-temporal atrophy and functional
neuroimaging shows relatively reduced blood flow to anterior temporal and frontal regions (SPECT) or reduced glucose
metabolism (PET) in the same anatomic distribution. These features are compatible with the frontal or temporal lobar
atrophy found on postmortem examination of the affected brain. Neuronal degeneration is the characteristic
neuropathologic change of FTD. Manifestations of Pick's disease also include argyrophilic neuronal inclusions (Pick
bodies), with or without balloon cells.[29]
Diagnostically, functional imaging studies may help distinguish FTD from AD. Again, although SPECT or PET
demonstrate selective reductions in cerebral perfusion or metabolism of the anterior hemispheric regions in FTD, these
same abnormalities are preferentially in the posterior hemispheric regions in AD.[30]
Subcortical degenerative disorders
The clinical features of AD and FTD (aphasia, amnesia, apraxia, agnosia) reflect the predominantly cortical involvement
of these disorders. There is another group of degenerative disorders that cause dementia with predominant involvement of
subcortical structures (basal ganglia, thalamus, cerebellum, and rostral brainstem). The major disorders in this category
include Parkinson's disease, Wilson's disease, progressive supranuclear palsy, Huntington's disease, Fahr's disease
(idiopathic basal ganglia calcification), multisystem atrophies, and thalamic dementia. Approximately 40% of patients
with Parkinson's disease have overt dementia and up to 70% have more subtle neuropsychological deficits. The
neuropsychological features of subcortical disorders include disturbances in attention and concentration, poor motivation,
slowed information-processing speed, and memory disturbances. Patients appear depressed and apathetic, with
psychomotor slowing. On memory testing, they have retrieval failures but improve with cues. This memory deficit is
often accompanied by disturbances of executive functions, including problem solving and strategy formulation.[31] Unlike
AD and FTD, movement disorders are prominent in the subcortical dementia syndromes. Depending on the specific
disease state, patients may present with a hypokinetic, rigid parkinsonian state or a hyperkinetic, choreic, dystonic, or
ataxic disturbance ( Table 25.2 ).
Table 25.2 -- Major clinical features of the principal dementia syndromes
Syndrome
Features
Alzheimer's disease
Gradual onset and progression, aphasia, amnesia, apraxia, agnosia, executive dysfunction,
visuospatial impairment, concreteness, indifference, preserved motor function
Syndrome
Features
Frontotemporal
dementia
Gradual onset and progression, aphasia, apraxia, agnosia, executive dysfunction, relative retention
of memory and visuospatial skills until later stages, personality changes such as Kluver-Bucy
syndrome, disinhibition, apathy, atypical depression, preserved motor function
Subcortical
syndromes
Gradual onset and progression, psychomotor retardation, depression, forgetfulness, executive
dysfunction, extrapyramidal signs and symptoms
Dementia with
Lewy bodies
Gradual onset and progression, aphasia, amnesia, apraxia, agnosia, fluctuating severity, prominent
visual or auditory hallucinations, delusions, clouding of consciousness, extrapyramidal signs and
symptoms
Vascular diseases
Abrupt onset, stepwise progression, cortical and subcortical features, fluctuating course,
preservation of personality, emotional incontinence, depression, focal neurologic signs and
symptoms
Toxic-metabolic
conditions
Cortical and subcortical features, inattention, fluctuating arousal, peripheral neuropathy,
myoclonus, asterixis, tremor
Myelin disorders
Cortical and subcortical features, focal neurologic signs, mood disorders
Normal-pressure
hydrocephalus
Cortical and subcortical features, psychomotor retardation, apathy, inattention, poor memory,
ataxia, gait disturbance, urinary incontinence
Neoplastic
conditions
Cortical and subcortical features, signs of increased intracranial pressure, cranial nerve palsies
Traumatic
conditions
Cortical and subcortical features, memory loss, personality changes, focal neurologic signs
CNS infections
Cortical and subcortical features, focal neurologic signs, myoclonus, seizures, headache, fever or
signs of infection
Inflammatory
conditions
Cortical and subcortical features, systemic evidence of inflammatory process, increased erythrocyte
sedimentation rate, and other serologic abnormalities
Psychiatric disorders Subcortical features, depressed mood, psychomotor retardation, cognitive slowing, poor
motivation, executive dysfunction
Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is characterized by a pathologic accumulation of Lewy bodies in the brainstem and
cortex. The clinical syndrome consists of marked fluctuation in cognition, visual and auditory hallucinations, clouding of
consciousness, and mild spontaneous extrapyramidal symptoms. In some patients, severe extrapyramidal signs may first
emerge after exposure to standard neuroleptic agents. [32] [33] Unlike delirium, with which it shares some common clinical
features, DLB persists and becomes progressively worse. Pathologically, DLB is characterized by numerous neuritic
plaques, rare neurofibrillary tangles, and Lewy bodies in cortical and brainstem neurons. Several authors have argued that
DLB may be more common than has been historically reported and may be second to AD as a cause of dementia in the
elderly.
Vascular dementia
Dementia resulting from ischemic cerebral injury, or vascular dementia (VaD), is second in frequency to AD as a cause of
chronic progressive intellectual decline. The percentage of all cases of dementia caused by cerebrovascular disease has
been quoted in the range of 12% to 20%.[34] The neuropsychological deficits seen in patients with vascular dementia result
from ischemic damage to multiple areas within the cortex and subcortical structures. The clinical features of vascular
dementia are determined by the number, site, and volume of infarctions. There is often a temporal relationship between
the onset of cognitive loss and the emergence of neurologic signs or symptoms of stroke. Historical features typically
include an abrupt onset of deficits, stepwise progression of deficits, and fluctuation in the severity of symptoms. Relative
preservation of personality, with emotional lability, depression, somatic preoccupation, and nocturnal confusion, are often
noted. Patients typically show evidence of associated atherosclerosis (electrocardiographic changes, history of myocardial
infarction or angina, retinopathy), history of hypertension, and focal neurologic signs and symptoms. Gait ataxia,
parkinsonism, and urinary incontinence are not infrequent. A history of stroke or transient ischemic events further
supports the diagnosis of multi-infarct or vascular dementia. The ischemia scale (IS)[35] is a checklist of the clinical
features of multi-infarct dementia, including its onset, course, and neurologic and psychiatric findings. A score of 7 or
above for a given patient is considered compatible with a vascular origin for the patient's dementia. Despite a sensitivity
and specificity of 70% to 80% in separating vascular dementia from Alzheimer's disease,[36] the IS is less well equipped to
diagnose the comorbid occurrence of these two disorders in the same patient reliably. There is evidence that this scale
may overdiagnose vascular dementia in patients who are subsequently found to have AD.[37]
Several different clinical presentations of vascular dementia are possible, depending on the predominant site of
neuroanatomic involvement. Vascular dementia may be a consequence of multiple cortical infarctions, multiple
subcortical infarctions (lacunar state), ischemic injury to the deep hemispheric white matter (Binswanger's disease), or a
combination of these. Major depression and psychosis frequently occur in dementia because of cerebrovascular disease.[15]
In vascular dementia, CT scans may demonstrate multiple areas of lucency compatible with infarction. MRI is particularly
sensitive in that it shows increased signal intensity in areas of ischemic injury. EEG may reveal multifocal slowing.
Dementia resulting from stroke is most often associated with fibrinoid necrosis of arterioles resulting from sustained
hypertension. Other risk factors for the development of vascular dementia include diabetes mellitus, hypercholesterolemia,
cardiac embolization, and inflammatory vasculitides.
Metabolic and toxic dementias
Elderly patients may suffer from several systemic illnesses that predispose them to the development of chronic metabolic
encephalopathies. In most cases, metabolic or toxic disturbances of the central nervous system produce transient effects
on cognition (delirium). However, when these effects persist for an extended period, dementia is diagnosed. These chronic
confusional states accompany a wide variety of systemic disorders, including severe anemia, disturbances of the thyroid,
parathyroid, and adrenal axes, cardiac and pulmonary insufficiency, renal and hepatic disease, and vitamin deficiencies
(particularly deficiencies of vitamin B12 and niacin).
Toxic causes of dementia are of particular concern in the elderly because the aged consume disproportionately large
numbers of over-the-counter and prescribed medications. The alterations in drug metabolism, distribution, binding, and
excretion that accompany normal aging increase the risks of drug toxicity. In addition, with advanced age, the brain may
be more sensitive to the effects of drugs, even in the absence of excessive dosing or polypharmacy.[38] Agents that are
especially likely to cause chronic confusional states include tranquilizers, sedative-hypnotics, and centrally acting
antihypertensive agents. Long-term alcoholism and chronic use of other drugs also cause dementia. Similarly, chronic
exposure to industrial solvents and heavy metals may cause dementia accompanied by peripheral neuropathy.
Salient clinical features of the metabolic and toxic dementias include fluctuating arousal, inattention, and impaired
memory and orientation. Severe disturbances of language and of higher cortical functions such as agnosia or apraxia are
notably uncommon. Motor system disturbances such as myoclonus, tremor, and asterixis are frequently present, and EEG
demonstrates diffuse slow wave activity. With resolution of the responsible metabolic derangement or cessation of
exposure to the offending toxin, improvement of neuropsychological deficits is usually seen.
Myelin diseases with dementia
In the elderly, diseases affecting the white matter are decidedly less common than those affecting the cortical and
subcortical gray matter. However, there are several myelinoclastic disorders that may cause dementia in the elderly.
Secondary white matter disorders include Binswanger's disease, viral illnesses such as aquired immunodeficiency
syndrome (AIDS) dementia complex, and progressive multifocal leukoencephalopathy. Multiple sclerosis is the most
common demyelinating disorder, although it rarely begins after the fourth decade of life. The course is relapsing and
remitting and involves an accumulation of enduring neurologic deficits. Classic symptoms include optic neuritis,
myelopathy with spasticity and incontinence, cerebellar dysfunction, and internuclear ophthalmoplegia. Intellectual
decline accompanies these features in almost 50% of afflicted patients.[39] Psychiatric symptoms often noted are
depression and mania. Rarer white matter dementing diseases include metachromatic leukodystrophy,
adrenoleukodystrophy, cerebrotendinous xanthomatosis, membranous lipodystrophy, adult Schilder's disease,
Marchiafava-Bignami disease, and hereditary adult-onset leukodystrophy.[40]
Normal pressure hydrocephalus dementia
Hydrocephalic dementia is characterized clinically by the triad of dementia, ataxia, and urinary incontinence. The
dementia is typified by psychomotor slowing, bradyphrenia, inattention, impaired memory, apathy, and concreteness.
Symptoms usually evolve over several months to years. In normal-pressure hydrocephalus (NPH), cerebrospinal fluid
(CSF) obstruction occurs at the level of the arachnoid granulations responsible for absorption into the venous circulation.
This state, associated with normal intracranial pressure, results from trauma, subarachnoid hemmorhage, encephalitis, or
meningitis. In some cases, it may be idiopathic. CT or MRI confirms the presence of increased ventricular size in
hydrocephalus that is out of proportion to any cortical atrophy that may be evident. The pattern of CSF flow is studied by
radionuclide cisternography and CSF pressure monitoring.[13] If lumbar puncture helps improve gait in an affected patient,
the diagnosis of NPH is supported. Despite its frequent consideration in the differential diagnosis, NPH is a rare cause of
dementia. The triad of dementia, incontinence, and ataxia is more often a sign of vascular dementia than of NPH.
Hydrocephalus with increased intracranial pressure is seen in patients with brain tumors (see later, “Neoplastic dementias”)
or inflammatory conditions such as ependymitis or arachnoiditis. Symptoms of increased intracranial pressure include
headache, papilledema, nausea, emesis, and lethargy. Somnolence or coma may eventually result.
Neoplastic dementias
Neoplasms that arise from the brain or metastasize from extracranial tumors may cause dementia through direct
compression, hydrocephalus, infiltration of brain tissue, or increased intracranial pressure. Generally, clinical symptoms
arising from intracranial tumors are insidious in onset and gradually progressive. Over several weeks to months, patients
may experience lethargy, headache, depression, impaired concentration, and memory disturbance. Focal neurologic
symptoms may emerge; gait ataxia and incontinence are sometimes noted. Although some tumors such as a subfrontal
meningioma can cause dementia without other neurologic features, this is the exception rather than the rule.
Meningeal carcinomatosis, another cause of neoplastic dementia, results from neoplastic invasion of the meninges. It is
associated with neoplasms of the breast, lung, gastrointestinal tract, and malignant melanoma. Patients experience
increased intracranial pressure, cranial nerve palsies, and a chronic confusional state characterized by disturbed attention
and concentration.
Occult systemic neoplasms such as oat cell carcinoma of the lung and carcinomas of the ovary or breast have been
associated with dementia as a remote effect. Depression and anxiety also have been noted in the clinical presentation.
Patients with this type of paraneoplastic syndrome often have clinical evidence of cerebellar dysfunction or cerebellar
atrophy noted on neuroimaging studies. Seizures, myeloradiculopathy, and myopathy have also been described in patients
with this condition.
Traumatic dementias
Trauma to the brain often results in alterations in personality and enduring intellectual deficits, such as aphasia, amnesia,
apraxia, and concreteness. The inferior frontal lobes and medial temporal lobes are particularly susceptible to damage in
closed head injury. Such trauma may cause hemorrhage, laceration, contusion, and shearing injuries of neuronal axons. In
the elderly, the formation of subdural hematomas is of special concern. Affected patients may develop a chronic
confusional state with fluctuating attention and transient, minor focal neurologic signs. Dementia pugilistica has been
noted in older or retired boxers following repeated blows to the head. The dementia is accompanied by ataxia and
extrapyramidal dysfunction.
Infection-related dementias
Several different types of infections of the nervous system can produce dementia. Bacterial infection usually causes an
acute encephalopathy (delirium) rather than a chronic confusional state or dementia. General paresis (neurosyphilis) is a
chronic spirochetal infection characterized by dementia with prominent frontal lobe signs. Neuroborreliosis (central
nervous system Lyme disease) is another cause of dementia that may or may not have been preceded by the classic targetlike lesion and erythema migrans. Whipple's disease is a poorly understood and uncommon bacterial infection affecting
the central nervous system that is characterized by meningeal signs, dementia, supranuclear gaze palsy, and systemic
symptoms (e.g., lymphadenopathy, malaise, diarrhea, fever, arthralgia). Diagnosis depends on jejunal biopsy
demonstrating characteristic macrophage infiltration and CSF evaluation.
Chronic meningitis can result from fungal, protozoan, or helminthic infection. This can cause a chronic confusional state,
with increased intracranial pressure and cranial nerve abnormalities.
Acute viral infections such as herpes encephalitis may cause a persistent postencephalitic dementia if the injury to the
central nervous system (CNS) is severe. Viruses may also cause dementia through a slowly progressive encephalitis. Slow
viral dementias include AIDS dementia complex, subacute sclerosing panencephalitis, and progressive multifocal
leukoencephalopathy. AIDS dementia complex results from direct infection of the brain by the human immunodeficiency
virus (HIV). Clinically, affected patients present with apathy, depression, psychomotor slowing, forgetfulness, and
dilapidated cognition.[41] Headache is a common associated feature. Neurologic symptoms such as motor signs and
unusual movements may be noted. Opportunistic infections of the CNS (e.g., toxoplasmosis, cryptococcal infection, and
tuberculosis) occur in patients with AIDS and may also cause or exacerbate dementia.
Creutzfeld-Jakob disease (CJD) is a potentially transmissible disorder with onset in the fifth to seventh decades. It has
been linked to an infectious membranous protein called a prion. The course is rapidly progressive and leads to death
within several months. Patients manifest a progressive dementia, myoclonus, and pyramidal and extrapyramidal signs.
During the course of the illness, EEG shows periodic spike discharges, with background slowing in most patients.
Recently, worldwide attention has focused on the emergence of progressive bovine spongiform encephalopathy (variant
CJD, mad cow disease), a scrapie-like prion disorder causing rapidly progressive neurologic deterioration and dementia in
susceptible persons exposed through eating infected meat.[42]
Progressive multifocal leukoencephalopathy results from papovavirus CNS infection in immunocompromised patients.
The virus has its greatest pathologic impact on the cerebral white matter.
Inflammatory dementias
Systemic autoimmune disorders such as systemic lupus erythematosis, sarcoidosis, and temporal arteritis may result in
dementia through vascular occlusion and direct inflammatory and immunologic effects on brain parenchyma. Diagnosis
depends on an elevated erythrocyte sedimentation rate and confirmatory serologic abnormalities.
Psychiatric disorders with dementia
In the past, significant attention was paid to the presence of dementia in depressed elderly persons. This was called
depressive pseudodementia, but is now referred to as the dementia syndrome of depression; it has been closely linked to
subcortical cerebrovascular disease, especially white matter lesions on MRI.[43] Many of these patients will go on to
develop vascular dementia or AD. It has also been reported that patients with late-onset depression have reduced
hippocampal volumes, further suggesting vulnerability to the subsequent development of AD.[44] The syndrome of
depression and dementia most prominently includes forgetfulness, psychomotor retardation, poor motivation, executive
dysfunction, and cognitive slowing. Patients have incontrovertible evidence of depressed mood and may have a personal
or family history of depression. Following treatment of the depression, neuropsychological improvement is noted.
Interestingly, patients with a history of the onset of depression in late life appear to be at increased risk for the subsequent
development of dementia.[45] Additionally, Cannon-Spoor and colleagues reported that AD patients with a prior history of
major depressive episode appeared to have more severe cognitive deficits during the actual course of dementia than
patients without such a history.[46]
Dementia has been identified occasionally in other psychiatric disturbances, such as acute mania and schizophrenia. [47]
Evaluation of dementia
Comprehensive evaluation of acquired intellectual impairment and associated behavioral and mood disturbances has
several purposes: (1) to establish the cause for dementia; (2) to guide appropriate treatment; (3) to identify reversible or
treatable concurrent medical illnesses; (4) to determine prognosis; (5) to facilitate education and counseling of family
members; (6) to provide genetic advice, where appropriate; and (7) to identify pertinent psychosocial stressors and family
concerns that directly affect caregiving. To accomplish these goals most effectively, a thorough assessment consisting of a
careful medical and psychiatric history, physical, neurologic, and mental status examinations, laboratory evaluation and,
often, neuroimaging procedures is mandatory ( Table 25.3 ).
Table 25.3 -- Standard evaluation of dementia
History
History of illness
Review of systems
Past medical history
Medication review
Family history
Psychiatric history
Physical examination
Neurologic examination
Mental status examination (with rating of dementia severity)
Laboratory assessment (mandatory)
Complete blood count with differential
Levels of electrolytes, blood urea nitrogen, creatinine, blood glucose, serum calcium
Liver function tests
High-sensitivity thyroid-stimulating hormone
Serum vitamin B12
Laboratory assessment (selective)
Erythrocyte sedimentation rate
Human immunodeficiency virus antibody
Syphilis serology
Lyme disease antibody titer
Endocrine studies (e.g., serum cortisol, parathyroid hormone levels)
Rheumatologic studies (e.g., rheumatoid factor, antinuclear antibody titer)
Arterial blood gas determination
Serum homocysteine level
Neuroimaging (usually necessary)
Computed tomography or magnetic resonance imaging of the head
Neuroimaging (selective)
Positron emission tomography
Single-photon emission computed tomography
Ancillary studies
Lumbar puncture
Electroencephalography
Electrocardiography
Neuropsychological evaluation
Chest radiography
Apolipoprotein E4 testing
The Mini-Mental State Examination (MMSE)[48] provides a brief method for recording and following the changes in the
cognitive state of the patient with dementia. The addition of a clock drawing test and a test of verbal fluency (categorical
naming) can improve the sensitivity of the MMSE as a screening measure in a primary care setting.
No battery of laboratory tests is completely applicable to all demented patients. Individualized investigations are dictated
by the particular constellation of signs and symptoms presented. However, in all patients with dementia, certain initial
studies should be done. Routine tests of greatest diagnostic use include a complete blood count, serum electrolyte levels
(including calcium, serum glucose, creatinine, blood urea nitrogen, bilirubin, and alkaline phosphatase), vitamin B12 level,
and thyroid function tests (especially thyroid-stimulating hormone). If pertinent risk factors are identified and the clincial
state is compatible with AIDS dementia, antibody testing may be indicated. In the presence of the appropriate clinical
history, serologic tests for Lyme disease or syphilis may be warranted. Lumbar puncture may be appropriate if CJD or a
demyelinating disorder is suspected, the dementia syndrome is atypical, or there is evidence of infection or inflammation
of the central nervous system (e.g., headache, meningeal signs, fever, seizures).
A structural neuroimaging study such as MRI or CT scanning of the head is a necessary component of most evaluations of
dementia. MRI offers more accurate structural anatomic and pathologic assessment but is more time-consuming and
costly to perform. It cannot be used in patients who have a pacemaker or metallic intracranial objects, such as surgical
clips. Whichever study is selected, MRI or CT adds to diagnostic precision by detecting stroke, mass lesions, areas of
demyelination, hydrocephalus, or atrophy. The routine applicability of newer modalities such as SPECT or PET awaits
further confirmation. However, PET may be especially useful in helping distinguish FTD from AD. EEG is helpful
diagnostically when infections, Creutzfeldt-Jakob disease, inflammatory disorders, or toxic-metabolic causes of dementia
are under consideration. Additionally, EEG is needed for the evaluation of seizure activity. CSF analysis of tau protein or
beta amyloid is discouraged until additional data regarding the sensitivity and specificity of these tests emerge.
Currently, formal genetic testing and genetic counseling in dementia assessment are largely confined to the evaluation of
early-onset familial AD. In patients meeting diagnostic criteria for late-onset AD, determination of the individual patient's
apo E status is of limited additional diagnostic value and is thus not routinely recommended. Whether the test is reliable in
distinguishing AD as the cause of the patient's dementia from other, non-Alzheimer's causes is controversial and unsettled
at present. Tsuang and colleagues[49] examined this issue in some depth in a community-based case series in which clinical,
neuropathologic and apo E genotype were determined in 132 patients who underwent evaluation for dementia and
subsequent autopsy. They reported that the clinical diagnosis of AD alone yielded positive and negative predictive values
of 81% and 56%, respectively. Using the presence of a clinical diagnosis of AD with the addition of an apo E4 allele gene
test result yielded positive and negative predictive values of 88% and 40%, respectively.[49] Genetic testing for the apo E
allele in asymptomatic family members of patients with late-onset AD is not recommended because the test has
inadequate predictive value for the subsequent development of dementia. Concerns have also been raised about the
potential discriminatory effects of such test results on health benefit coverage, employment, and other social and financial
issues. The psychological effects of genetic test results on the individual are also worthy of consideration and thoughtful
management.
The role of cerebral biopsy in the evaluation of dementia is restricted. This procedure rarely leads to the diagnosis of a
reversible condition and often results in substantial morbidity.[50] Cerebral biopsy is most often justified in the evaluation
of Creutzfeldt-Jakob disease when special precautions may be needed to limit transmission during postmortem study.[51]
However, cerebrospinal testing for the CJD-associated 14-3-3 protein may be sufficient.[52]
Management of dementia
The neuropsychological deficits, neuropsychiatric symptoms, and medical illnesses that afflict demented patients pose
significant clinical challenges for physicians and caregivers. Effective treatment and management involve pharmacologic
and nonpharmacologic interventions.
Restoration and stabilization of intellectual function
Pharmacotherapy
At present, no single pharmacologic agent has shown clear efficacy in reversing or halting the intellectual deterioration
accompanying the two most common dementia syndromes, AD and vascular dementia. Practice guidelines and parameters
from the American Academy of Neurology,[53] the American Psychiatric Association,[54] and a consensus panel convened
by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society[55]
have all identified cholinesterase inhibitors (ChEIs; tacrine, donepezil, rivastigmine, and galantamine) as the standard of
care in AD. Numerous short- and long-term placebo-controlled trials of these medications conducted worldwide have
demonstrated their modest efficacy in improving cognition, behavior, and function in patients with mild to moderate
dementia severity. [56] [57] There is also evidence that functional decline and admission to nursing homes might be delayed
in some patients.[58] Data have also emerged to suggest that these agents may be of benefit in more moderate to severe
AD[59] and in conditions such as vascular dementia,[60] dementia with Lewy bodies,[61] and dementia associated with
Parkinson's disease.[62] Despite the reporting of much supportive data from studies conducted worldwide, the putative
benefits of ChEI therapy in AD have continued to undergo substantial scrutiny and have been a source of relatively recent
controversy. [63] [64] Because tacrine was found to produce liver function abnormalities and required serum studies when the
dose was increased, its use has been largely abandoned. As a class, the remaining ChEIs are generally well tolerated, but
individual agents differ somewhat in mechanism of action, dose titration requirements, and the propensity to cause side
effects ( Table 25.4 ). All ChEIs can cause cholinergic-related side effects, such as gastrointestinal distress (nausea,
vomiting, diarrhea).
Table 25.4 -- Medications to treat Alzheimer's disease
Mechanism of action
Starting dose
(mg)
Target dose (mg)
Cholinesterase inhibitor
5 qd
5-10 qd
Cholinesterase inhibitor
1.5 bid
3-6 bid
Galantamine[*] Cholinesterase inhibitor; allosteric modulator at
nicotinic receptor
4 bid
8-12 bid (16-24 qd extended
release)
Memantine[†]
5 qd
10 bid
Agent
Donepezil[*]
Rivastigmine
[*]
Noncompetitive, NMDA receptor antagonist
NMDA, N-Methyl-D-aspartate.
*
Indicated for mild to moderate Alzheimer's disease.
†
Indicated for moderate to severe Alzheimer's disease.
A large placebo-controlled trial in patients with moderate to severe AD demonstrated the ability of vitamin E therapy to
delay nursing home placement and functional disability.[65] Together with epidemiologic evidence that has suggested a
protective effect of antioxidants, including vitamin E, on the development of AD,[66] treatment guidelines have
recommended the adjunctive use of this agent with ChEIs. However, recent studies have called into question the efficacy
of vitamin E in enhancing or protecting cognition in the elderly.[67]
Memantine, an N-methyl-d-aspartate (NMDA) receptor, noncompetitive antagonist, is now indicated for use in moderate
to severe AD. It has a different mechanism of action than the cholinergic agents. Memantine acts to attenuate the
neurotoxic effects of excessive synaptic glutamate. Like the ChEIs, its clinical effects are modest and consist of some
delay in disease progression.[68] When combined with donepezil in the treatment of AD, symptomatic improvement has
also been noted.[69]
Other agents that have been the subject of study in the prevention and treatment of AD include estrogen, statins, and
NSAIDs. Ginkgo biloba has been shown to have modest effects on cognition in AD and is not presently recommended as
a therapeutic or preventive agent.
In vascular dementia, optimal control of hypertension and hyperlipidemia, and cessation of smoking help prevent
recurrent stroke; many clinicians advocate the use of one enteric-coated aspirin daily to diminish the risk further. ChEIs
have been shown to be of benefit in pure VaD as well as in the mixed state, in which VaD is thought to occur
concomitantly with AD.[70]
For the other nondegenerative dementing disorders, improvement in cognitive function following therapy is rarely
complete. Replacement of vitamin B12, ventricular shunting for patients with NPH, or correction of hypothyroidism often
leads to symptomatic improvement, but rarely to complete recovery. Importantly, these interventions can halt disease
progression and are thus of considerable benefit.
Nonpharmacologic techniques
Several nonpharmacologic techniques can aid caregivers and physicians in helping the demented patient to remain as
functional as possible throughout the course of the illness. These include the following: (1) maintaining eye contact and
speaking to the patient in a simple, distinct, and calm manner; (2) asking only one question at a time, and allowing ample
time for a response; (3) establishing a regular, structured daily routine while encouraging the patient's active participation;
(4) calmly reorienting the patient when necessary; (5) breaking down all tasks into several simple steps; and (6) setting
realistic expectations for what the patient can and cannot do.
Management of neuropsychiatric symptoms
In contrast to the largely unsuccessful experience in arresting or reversing the intellectual deficits of AD and vascular
dementia, many psychiatric and behavioral disturbances commonly encountered in these patients are directly amenable to
nonpharmacologic and pharmacologic interventions.
Nonpharmacologic interventions
Nonpharmacologic interventions for anxiety and psychosis include gentle reassurance and distraction. It is rarely helpful
to attempt to convince patients that their beliefs are false or that they are hallucinating. Such confrontation by the
caregiver or physician can escalate any concomitant agitation.
Occasionally, demented patients may become agitated or aggressive. If the patient is physically violent, caregivers should
remove any potentially dangerous objects and ensure their own safety. If distraction or reassurance does not improve the
patient's behavior, medication may be the only available option.
Pharmacologic interventions
For the treatment of psychosis and agitation, atypical antipsychotic medications are often used. They have largely
replaced conventional neuroleptics such as haloperidol, thiothixene, and thioridazine, given the tendency of such agents to
worsen confusion and cause extrapyramidal symptoms, including tardive dyskinesia. Some studies have supported the
efficacy and tolerability of risperidone[71] and olanzapine[64] in treating dementia-associated psychosis, aggression, and
agitation. A recent meta-analysis of the use of these agents for dementia has demonstrated their modest but significant
therapeutic effects in the care of elderly patients with dementia and behavioral symptoms.[72] Some limited data exist
indicating that other atypical antipsychotic agents such as quetiapine and aripiprazole may also confer some therapeutic
benefit. Although less likely to cause extrapyramidal side effects than their conventional neuroleptic agent predecessors,
the use of these newer agents should be initiated with care.
Recently, significant concern has been raised that the use of atypical antipsychotics for behavioral disturbances in
demented elderly patients is associated with a 1.6- to 1.7-fold increase in mortality.[73] This is on the basis of data from 17
placebo-controlled trials (four of which have been published) with olanzapine, risperidone or quetiapine. The specific
causes of death were heart-related (e.g., heart failure or sudden death) or infection (e.g., pneumonia). Mortality over the
course of a typical 10-week trial was approximately 4.5% in the drug-treated subjects versus 2.6% in the placebo group.
Additionally, there is some evidence that atypical antipsychotics may carry an additional risk for cerebrovascular adverse
events and glucose intolerance (metabolic syndrome) in treated patients. Consequently, this class of agents should be used
with caution and with fully informed consent of the patient or by a legal proxy. Prior to their use, nonpharmacologic
interventions should be tried. If the behavioral disturbance does not include overt delusions or hallucinations,
nonantipsychotic agents should be used first, although data supporting their efficacy are limited. In patients with mild
anxiety or restlessness, moderately short-acting benzodiazepines such as oxazepam 10 to 15 mg PO once or twice daily or
lorazepam 0.25 to 1 mg PO once or twice daily may be useful. The pharmacologic management of nonpsychotic agitation
or combativeness may include the use of anticonvulsants such as sodium valproate[74] and serotonergic compounds such as
citalopram[75] and sertraline.[76] Cholinesterase inhibitors may decrease apathy, psychosis or agitation in some patients.[77]
Pharmacologic management of depression and other mood disturbances in patients with dementia is similar to that used
for the nondemented elderly patient. Initially, physical contributors to the alteration in mood state should be investigated,
such as coexisting medical illnesses and drug or medication toxicity. Patients' feelings about their loss of intellectual
ability and autonomy, social isolation, financial problems, and guilt about increased caregiver burden need to be
thoroughly explored and addressed. While these issues are being addressed, pharmacologic treatment can be directed to
target symptoms such as dysphoric mood and disturbances of sleep, appetite, and energy. Treatment with antidepressant
agents with few anticholinergic side effects such as citalopram, sertraline, fluoxetine, paroxetine, buproprion, venlafaxine,
or mirtazapine may afford some relief without producing additional confusion. Pharmacotherapy should be initiated with
the lowest possible dose and upward titration performed judiciously.
Patients with dementia frequently have sleep disturbances. They may be restless or wander aimlessly in the night. Initial
interventions should be directed toward improving sleep hygiene. Widely accepted therapeutic tactics include the
following: (1) avoiding caffeinated beverages and medications with stimulant effects in the afternoon or evening; (2)
limiting eating or watching television in bed, encouraging only sleeping; (3) discouraging excessive intake of fluids in the
evening to prevent nocturia; (4) investigating other medical causes of insomnia such as pain, cardiac, or pulmonary
disease or restless legs syndrome; and (5) discouraging daytime naps. When these interventions are not sufficient to
restore adequate sleep, pharmacotherapy is indicated. Although no particular hypnotic agent has demonstrated superior
efficacy in patients with dementia, sedating antidepressant agents such as mirtazapine or trazodone are often used. Shortacting sedative-hypnotics such as oxazepam (10 to 30 mg PO), lorazepam (0.5 to 2 mg PO), and zolpidem (5 to 10 mg PO)
may be helpful if given 1 hour before bedtime. If these agents are used for prolonged periods, however, patients may
experience early morning awakening. Long-acting benzodiazepines such as diazepam are best avoided because their
metabolites often accumulate, leading to daytime drowsiness or increased confusion. A sedating atypical antipsychotic
agent such as quetiapine or olanzapine may be beneficial in treating nocturnal agitation ( Table 25.5 ).
Table 25.5 -- Pharmacologic treatment of neuropsychiatric symptoms
Agent
Class
Dose range Uses
Side effects
Lorazepam
Benzodiazepine
0.25-2
mg/day
Anxiety, restlessness,
insomnia
Sedation, ataxia, confusion
Oxazepam
Benzodiazepine
5-10
mg/day
Anxiety, sedation, ataxia,
restlessness
Confusion, insomnia
Zolpidem
Nonbenzodiazepine
hypnotic
5-10 mg HS Insomnia
Sedation, confusion
Risperidone Atypical antipsychotic
0.25-2
mg/day
Psychosis, agitation
Sedation, EPS, cerebrovascular
event, hypotension
Olanzapine
Atypical antipsychotic
5-10
mg/day
Psychosis, agitation
Sedation, EPS, cerebrovascular
event, hypotension
Quetiapine
Atypical antipsychotic
25-200
mg/day
Psychosis, agitation
Sedation, EPS, hypotension
Aripiprazole Atypical antipsychotic
5 – 15
mg/day
Psychosis, agitation
Sedation, EPS, hypotension
Sertraline
Antidepressant
25-200
mg/day
Depression, anxiety,
irritability
Loose stools, sedation
Citalopram
Antidepressant
10-40
mg/day
Depression, anxiety,
irritability
Sedation
Mirtazepine Antidepressant
15-30
mg/day
Insomnia, depression
Sedation, weight gain, anxiety
EPS, Extrapyramidal signs and symptoms.
Caregiver issues
Ongoing surveillance and treatment of caregiver stress and depression are of paramount importance for the successful
management of the demented patient. Identification and participation of other potential caregivers should be encouraged.
When feasible, primary caregivers should be encouraged to attend caregiver support groups while lessening their own
burden of responsibility through the use of additional assistance such as daycare, respite, or home health aides. Referral of
caregivers to organizations such as the Alzheimer's Association is often helpful (1-800-272-3900; www.Alz.org ).
Early in the course of the dementia, referrals should be made for financial and legal counseling. Additionally, caregivers
should be educated about the signs and symptoms of potentially complicating medical problems, such as urinary tract
infection and incontinence. Simple strategies, such as beginning a regular toileting schedule, using adult diapers, and
monitoring fluid intake, can aid in the successful management of urinary incontinence. Over time, information should also
be gathered about the family's attitudes toward nursing home admission, and appropriate advice about this issue should be
given as needed.
Chapter 26 – Delirium
Summary Points for the Primary Care Physician
•
Screen all older patients admitted to the hospital with a daily mental status examination.
•
Prescribe cautiously and watch for cognitive side effects of medications.
•
Delirium is a medical emergency; assess patients rapidly.
•
Treat all underlying causes. Delirium is often multifactorial.
•
Cerebral imaging is of limited diagnostic benefit unless there is an abnormal neurologic examination.
•
Management of agitation does not address the underlying delirium and may prolong the duration of delirium.
•
Screen patients with delirium for nosocomial complications (e.g., pressure ulcers, aspiration and/or
pneumonia).
•
Strategies to prevent delirium are effective.
Summary Points for the Primary Care Physician
To effectively treat the patient the clinician should:
•
Reexamine the patient.
•
Recognize delirium.
•
Refrain from coming to closure too quickly—the cause is often multifactorial.
•
Treat the underlying disease.
•
Recheck the medication list.
•
Reorient the patient.
•
Remove restraints and tethers.
•
Reestablish the sleep-wake cycle.
•
Recover glasses and hearing aids from the drawer or safe and replace on the patient.
•
Rehydrate and renourish the patient.
•
Rehabilitate the patient (physical therapy).
•
Resist starting new therapies.
Delirium is a common, morbid, and costly syndrome that occurs preferentially in older patients with cognitive impairment,
sensory impairment, or multiple comorbidities. In geriatric outpatients, the prevalence of delirium can be up to 7%. On a
general medical ward, the prevalence of delirium is 10% to 15% on hospital admission and the incidence is 15% to 25%
after admission, yielding a total prevalence of 25% to 40% in older inpatients.[1] Delirium is associated with as much as a
tenfold increase in hospital mortality. Additionally, delirious patients have increased length of stay,[2] greater staff (e.g.,
physicians, RNs, LPNs) time requirements, and higher rates of nursing home placement,[2] all of which represent
significant costs to the health care system. Despite these factors, 32% to 67% cases of delirium are unrecognized by
physicians. Delirium can be prevented with cost-effective intervention protocols. [3] [4]
Delirium is a syndrome with many names. At times, mental status symptoms may be recognized but not appropriately
evaluated because of this lack of standardized nomenclature. Box 26.1 provides a partial list of the names used in the
medical literature to describe delirium. Names vary from the common “change in mental status” to the obscure “subacute
befuddlement.” Of the diagnoses listed in Box 26.1 , only delirium has a billable International Classification of Diseases,
9th Revision (ICD-9) code. Thus, the correct nomenclature is important for standardizing the diagnosis of delirium and
recognizing the true cost of delirium to the medical care system and the patient.
BOX 26.1
Terms Used in the Medical Literature to Describe Delirium
Acute confusional state
Acute mental status change
Altered mental status
Dysergastic reaction
Metabolic encephalopathy
Organic brain syndrome
Reversible cognitive dysfunction
Reversible dementia
Reversible toxic psychosis
Subacute befuddlement
Toxic confusional state
Toxic-metabolic encephalopathy
Toxic psychosis
Diagnosis
The diagnosis of delirium can be challenging, especially with coexisting dementia or depression. However, a diagnostic
algorithm, the confusion assessment method (CAM), based on the criteria set forth in the Diagnostic and Statistical
Manual of Mental Disorders, third revised edition,[5] has been validated for the clinical diagnosis of delirium.[6] In
combination with mental status testing, the CAM has become the gold standard for the diagnosis of delirium. The CAM
algorithm is shown in Figure 26.1 , and its criteria are delineated here. The diagnosis of delirium by CAM requires that
the patient demonstrate criteria 1 and 2 and either 3 or 4.
Diagnostic criteria
Criterion 1: acute onset and fluctuating course
The mental status changes in delirium develop over hours to days and represent a decline from the previous level of
cognitive functioning. Delirious patients may have fluctuating periods of relative lucidity and confusion over the course of
a day. Because physicians are not with patients throughout the day, a history for criterion 1 is better obtained from family,
caregivers, or nurses.
Criterion 2: inattention
Attentional disturbances such as distractibility, failure to keep track of the conversation, or perseveration on a previous
question are challenging to assess without formal attention assessments to supplement the clinical interview. Formal
assessment instruments include serial sevens, digit span backward, months of the year backward, or days of the week
backward. Serial sevens, where the patient counts backward in sevens from 100, has significant educational bias and
performance is less likely to be indicative of pure attention than the other tasks described.
Criterion 3: disorganized thinking
Disorganized thinking is often recognized by the clinician but dismissed as baseline personality traits, dementia, or sleep
deprivation; these patients are the classic “poor historians.” Illogical flow of ideas, irrelevant conversation, or speech or
language disturbances by the patient satisfies the criterion for disorganized thinking. Disorganized thought can be verbose
and illogical or scant and perseverative. Disturbance of thought should not be dismissed, particularly in the older
hospitalized patient.
Criterion 4: altered level of consciousness
An altered level of consciousness can be detected by holding a short conversation with the patient and assessing whether
the patient is alert, hypervigilant, lethargic, or stuporous. Any level of consciousness other than alert is considered
abnormal. Regardless of sleep deprivation or medication administration, it is not normal for a patient to fall asleep
repeatedly during the clinical interview. Such behavior would be indicative of an abnormal level of consciousness.
Delirium subtypes
The delirious patient can present with one of three delirium subtypes: hyperactive (25% of delirious patients), hypoactive
(50%), or a mixed hyperactive-hypoactive disorder (25%). Providers frequently fail to recognize patients with hypoactive
delirium, because the patient does not cause any behavioral disturbances that bring him or her to the provider's attention.
Moreover, busy providers spend less time at the bedside talking to patients, and hypoactive delirium may not be obvious
in the casual conversation that frequently occurs ( Box 26.2 ).
BOX 26.2
How to Recognize Delirium During a Conversation
A conversation might proceed in this way:
MD: “How are you today, Mr. Smith?”
Mr. Smith: “OK.”
However, this does not rule out a potentially serious delirium.
•
Health care providers frequently fail to recognize patients with hypoactive delirium because the patient does
not cause behavioral disturbances that might bring him or her to the provider's attention.
•
Patients with hyperactive delirium are at risk for oversedation and restraint use, particularly when these efforts
are combined with a failure to evaluate and treat the cause of the delirium.
•
When an acute change in mental status occurs, the diagnosis of delirium should be presumed until proven
otherwise.
Delirium should be considered a medical emergency and should be promptly assessed and treated.
Because hypoactive delirium is so frequently missed, these patients are at risk for delayed diagnosis and a prolonged
course. On the other hand, patients with hyperactive delirium are rarely missed because of their disruptive behavior. The
primary risk in these patients is associated with oversedation and restraint use, particularly when combined with a failure
to evaluate and treat the underlying cause of the delirium. Mixed disorder patients may “sundown” by staying awake at
night and sleeping during the day. There is little difference among the subtypes with respect to morbidity and mortality.
However, the subtype does affect the ability to assess the patient and the resources needed for management. Regardless of
the subtype, evaluation of the patient and treatment of underlying causes are critical.
Differentiating delirium, dementia, and depression
Many disorders can have clinical features of delirium and patients with delirium are often mistakenly diagnosed with
dementia or depression. The acute onset of delirium over hours to days highlights an important distinction not present in
dementia and depression, which develop over months to years. Inattention is a distinguishing feature between delirium
and dementia. Attention is spared in early and moderate dementia, whereas it is always impaired in delirium. Altered
levels of consciousness should not be present in mild or moderate dementia or depression. However, patients with severe
dementia or depression may have chronically altered consciousness. Finally, delirium, dementia, and depression can
coexist within the same patient. When an acute change in mental status occurs, the diagnosis of delirium should be
presumed until proven otherwise.
Pathophysiology
Current theories have been derived from clinical observation and are being investigated in the laboratory. A major
challenge in this field is the heterogeneity of the delirium syndrome and the populations in which it is studied. Early data
suggest that different underlying mechanisms may be applicable in different situations.[7]
Three of the various mechanisms of delirium have received particular attention. The first is that delirium represents a state
of acute central cholinergic failure. The clinical observation of delirium in patients with anticholinergic poisoning—mad
as a hatter—has prompted the cholinergic failure hypothesis. This led to the subsequent development of an assay to
measure serum anticholinergic activity. Several small studies have demonstrated a strong association between serum
anticholinergic activity levels and delirium in medical and surgical patients. [8] [9] Additional studies must be performed to
correlate the level of serum anticholinergic activity with the incidence, persistence, and resolution of delirium.
A second potential mechanism for delirium relates to acute central serotonin deficiency. Serotonin is derived from
tryptophan, which competes with other large neutral amino acids (LNAAs) for transport across the blood-brain barrier
(BBB). During catabolic states, such as postsurgery or sepsis, there is a massive release of LNAAs, which are relatively
tryptophan deficient. Phenylalanine, a dopamine precursor, has the highest affinity for the LNAA transporter and
competitively inhibits the LNAA receptor, resulting in a relative serotonin deficiency, which in turn may result in
delirium.[10] Accordingly, high levels of phenylalanine (common in postoperative or posttraumatic catabolic states) and
low tryptophan-to-phenylalanine ratios have been associated with delirium.[11]
The final clinical observation is that delirium occurs most frequently during times of systemic stress when the
inflammatory response is heightened. There is an increase in circulating inflammatory markers with age and regulation of
inflammation is diminished in older patients. Administration of interleukin-1 (IL-1), a proinflammatory cytokine,
increases acetylcholinesterase production and activity, causing a relative cholinergic deficiency. When IL-1 is
administered to rodents, symptoms of psychomotor retardation, altered sleep-wake patterns, and decreased responsiveness
are induced. Administration of IL-6 to rats increases BBB permeability, activates neuronal lymphocytes, and causes
impairments in learning. Studies of cancer and hepatitis C patients have demonstrated that interferon-α can slow
attentional functioning and precipitate delirium.
Research aimed at understanding the underlying mechanisms of delirium is in its infancy. More work is needed before
targeted pathophysiologically based preventive or treatment strategies can be designed.
Risk factors
Delirium is a complex syndrome that is rarely caused by one disorder; its has multifactorial causes. Predisposing
characteristics increase patient vulnerability to delirium and precipitating factors expose patients to an increased risk of
developing delirium. Table 26.1 summarizes predisposing and precipitating factors for delirium. Within this framework,
patients with many predisposing factors are at high risk for delirium, with minimal exposure to precipitating factors. For
example, an older male patient with dementia, extensive vascular disease, and visual impairment may develop delirium
with the single administration of a sleeping medication. Conversely, a patient with few predisposing factors might not
develop delirium unless exposed to a number of precipitating factors (e.g., severe illness, intensive care unit [ICU]
admission, multiple psychoactive medications, catheter-associated urinary tract infection).
Table 26.1 -- Risk factors for delirium
Predisposing factors Precipitating factors
Age
Catheter use
Alcohol abuse
Dehydration
Cognitive impairment Environmental change
Depression
More than three new inpatient medications
Increased comorbidity More than six total medications
Male gender
Iatrogenic event
Sensory impairment
ICU admission
Infection
Predisposing factors Precipitating factors
Psychotropic medication
Malnutrition
Restraint use
Predisposing factors
Although age has been demonstrated to be independently associated with delirium in hospitalized patients,[12] patients
should be assessed for risk factors other than age. Dementia and neurologic disorders (e.g., stroke, Parkinson's disease)
have been established as predisposing factors for delirium.[13] Depression can confound the diagnosis of delirium and is
also a risk factor for the development of delirium. [2] [14] Alcohol use is prevalent among the older population and increases
the risk of delirium through chronic brain effects and acute withdrawal. Impairments of vision or hearing limit the
environmental cues of the hospital and increase the risk of delirium.[15]
Precipitating factors
Medication use is a major precipitating factor for delirium. The addition of more than three new medications (of any type)
has been associated with delirium independent of age, cognition, and comorbidities.[16] Medications with neurologic or
cognitive mechanisms of action or side effects place patients at an even higher risk of developing delirium. Specifically,
the use of opioid analgesics,[12] especially meperidine,[17] long-acting benzodiazepines, diphenhydramine,[18] and
psychoactive medications,[12] has been independently associated with delirium. Patients with predisposing factors may be
particularly sensitive to medications, but almost any patient treated with enough psychoactive medications will develop
delirium.
Delirium can be precipitated as an unintended consequence of hospital care. Environmental changes, particularly
admission to the ICU,[19] dehydration (measured as a blood urea nitrogen–to–creatinine ratio higher than 18),[15] an
iatrogenic infection such as aspiration pneumonia or catheter-induced urinary tract infection, [12] [15] are associated with
delirium. Malnutrition from surgical or medical care, defined as a serum albumin level below 3 g/dL, can precipitate
delirium.[16] Additionally, the limitation of movement by physical or medical restraints (e.g., urinary catheters, oxygen
tubing, intravenous poles) can precipitate delirium.[16]
Special populations
Postoperative patients
Delirium occurring after surgery has many of the predisposing factors as those for medical patients. Although the
operation is usually the precipitating event, patients are at risk from precipitating factors (see earlier). The incidence of
postoperative delirium varies widely with the type of surgical procedure ( Table 26.2 ). It does not appear to be affected
by general, epidural, or spinal anesthesia.[20] After emergency or urgent surgical procedures, patients develop delirium
more frequently than those who undergo elective procedures. For example, patients with hip fractures are at increased risk
of postoperative delirium compared with those undergoing elective hip replacement. However, even in the high-risk hip
fracture population, delirium can be prevented using a proactive multifactorial protocol.[21]
Table 26.2 -- Incidence of delirium after surgery
Surgery
Incidence of delirium (%)
Abdominal aortic aneurysm repair
41-54
Hip fracture
35-65
Coronary artery bypass graft
32-50
Peripheral vascular bypass
30-48
Head and neck (major)
17
Elective orthopedic
9-15
Abdominal
5-26
Surgery
Incidence of delirium (%)
Urologic
4-7
Cataract
4
Surgery for atherosclerosis pathology, such as coronary artery bypass grafting (CABG), abdominal aortic aneurysm repair,
or peripheral vascular bypass is associated with an increased incidence of delirium (see Table 26.2 ). Some risk factors for
delirium are also risk factors for atherosclerosis, such as increased age,[22] male gender,[14] and hypertension.[23]
Additionally, atherosclerosis burden has been associated with delirium after CABG surgery.[24] Further investigation is
necessary to determine whether the increased risk of delirium is related to predisposing characteristics in the
atherosclerosis surgery population or precipitating factors during the surgical procedure.
Intensive care unit patients
In a study of delirium in older ICU patients, 31% of patients were admitted with delirium and 70% to 87% of patients
were delirious during the ICU hospitalization. [19] [25] Even among easily arousable ICU patients, 39% are delirious.[19]
Predisposing risk factors such as cognitive impairment and increasing severity of illness, as measured by the Acute
Physiology Age, Chronic Health Evaluation (APACHE-II) score are a risk factors in ICU patients.[25] Precipitating factors
in the ICU, such as sleep-wake interruptions, infection, and polypharmacy are hypothesized to lead to delirium.
Causes: Because delirium often has more than one cause, the practitioner should consider a number of underlying causes
( Table 26.3 ). Delirium may be the atypical presentation of a common disorder or an atypical reaction to medication.
Table 26.3 -- Causes of delirium[*]
Opioids, benzodiazepines; see Table 26.4
D Drugs
E Electrolytes
Hypernatremia or hyponatremia, hyperglycemia or hypoglycemia, other electrolyte
imbalance
L Lack of drugs, water, or food
Pain, withdrawal, dehydration, signs of malnutrition
I
Infection
R Reduced sensory input
I
Intracranial causes
Sepsis, urinary tract infection, aspiration pneumonia
Impaired vision, impaired hearing, neuropathy
Subdural hematoma, meningitis, seizure
U Urinary retention/fecal
impaction
Drugs, constipation
M Myocardial
Myocardial infarction, congestive heart failure, arrythmia
*
Delirium often has more than one cause.
Medications are the most common reversible cause of delirium. Table 26.4 highlights some medications known to
precipitate delirium. In older patients, toxicity can be present at therapeutic doses and atypical side effects are often the
presenting symptom of delirium. Special attention should be given to psychoactive medications with long elimination
half-lives and active metabolites. The odds of developing delirium are increased with the use of meperidine (odds ratio
[OR], 2.7) and benzodiazepines (OR, 3.0).[17] The use of diphenhydramine, a commonly used highly anticholinergic
antihistamine, also increases the risk of delirium (relative risk [RR], 1.7).[18] Medications with primary anticholinergic
mechanisms of action, such as those used for incontinence, muscle spasm, or gastrointestinal spasm, or antihistamines
(both H1 and H2 blockers), can increase the anticholinergic activity, which has been associated with delirium in small
studies of high-risk populations. [8] [9]
Table 26.4 -- Medications that can cause delirium
Class
Examples
Antiarrhythmic
Digoxin, procainamide, amiodarone
Comments
Lipophilic; cross BBB, alter membrane
physiology
Class
Examples
Comments
Antidepressant
Amitriptyline, imipramine
Anticholinergic with long-acting
metabolites
Antiepileptic
Phenytoin, divalproate, carbamazepine,
levetiracetam
Reduced therapeutic window
Antihistamine
Diphenhydramine, hydroxyzine, ranitidine
Anticholinergic; need to assess OTC use
Antipsychotic
Haloperidol, thioridazine
Anticholinergic and dopaminergic activity
Antispasmodic
Oxybutynin, cyclobenzaprine, belladonna
Mechanism of action is anticholinergic
Benzodiazepine
Diazepam, flurazepam, chlordiazepoxide
Especially longer acting benzodiazepines
Corticosteroid
Prednisone, dexamethasone
Cross BBB
Medication with actions in the Lithium, levodopa, indomethacin,
CNS
methyldopa
Cross BBB; alter neuronal function
Opioid
Meperidine more toxic than other opioids
Meperidine, proproxyphene, methadone,
codeine
BBB, Blood-brain barrier; CNS, central nervous system; OTC, over-the-counter.
In addition to the toxic effect of medications, delirium may be precipitated by the lack of medications. Undertreatment of
pain can contribute to delirium, but overtreatment with opioid medications can also precipitate delirium. The physician
and nursing staff should regularly assess pain and the effect of pain treatment using a validated pain scale. Patients should
be screened for alcohol use, because alcohol is metabolized to a lesser degree in the older patient. Thus, a lesser amount of
alcohol can create dependence and increase the risk for delirium from withdrawal.[2] Patients should also be screened for
withdrawal from other drugs taken on a regular basis, such as opioids, antidepressants, nicotine, and caffeine.
Delirium as the presenting symptom of systemic disease should be considered as well. Studies have found an association
with electrolyte abnormalities such as hypernatremia, hyperglycemia, and hypokalemia.[22] Patients with increased
severity of illness, as measured by the APACHE-II, caused by conditions such as sepsis, respiratory failure, or multiple
organ system dysfunction, are at increased risk of delirium.[15] Iatrogenic complications such as catheter-associated
urinary tract infection or aspiration pneumonia [12] [16] can present as delirium. Dehydration[15] and malnutrition[16] are
frequent complications of hospitalizations, and the presenting feature may be delirium.
Organ-specific causes of delirium also need assessment. Cardiac causes of delirium such as myocardial infarction,
congestive heart failure, or arrhythmia should be assessed. Patients with reduced sensory input from visual or hearing loss
are at increased risk for delirium[15] and hospital use of eyeglasses, hearing aids, and/or amplifiers has been shown to
improve sensory input, possibly preventing delirium.[26] The hospital environment itself can be toxic to patients
predisposed to delirium. The change in surroundings from home, unfamiliar faces, and frequent nighttime awakenings are
sufficient to precipitate delirium in a vulnerable patient. Additionally, urinary retention and fecal impaction, frequent side
effects of anticholinergic and opioid medications, have also been shown to cause delirium in elderly patients.
Evaluation and management
History and physical
Delirium should be considered a medical emergency and should be promptly assessed and treated. In the older patient, the
differential diagnosis for delirium is broad and therefore the history and physical examination are important. There is no
standard algorithm for the assessment of the delirious patient. Practitioners must use clinical acumen to guide workup and
management. “Summary Points for Treatment of Delirium for the Primary Care Clinician” at the beginning of the chapter
describes the steps that should be taken when evaluating the delirious patient. Delirium often has multifactorial causes, so
their assessment should continue throughout the differential diagnosis process, despite detection of a potential causative
disease process.
Accurate history information should be obtained from the patient, if possible. This should also be supplemented by
information from the family, caregiver, and nurse. The development of symptoms should be defined and compared with
the initiation of new therapies, environmental changes, and concurrent illnesses. An accurate history obtained with regard
to underlying cognitive deficits, sensory impairments, nutritional status, hydration, bowel movements, and urine output
can assist in narrowing the differential diagnosis. A thorough review of the medications received over the preceding days
is helpful, including over-the-counter medications and alcohol usage by outpatients.
Using clinical judgment, the clinician should perform a thorough physical examination, including a pain assessment. Vital
signs can provide clues, albeit nonspecific, to the underlying causes of delirium, such as low oxygen saturation readings
caused by pneumonia or congestive heart failure. Tachycardia can represent as an arrhythmia or be a response to fever,
pain, or drug withdrawal. The focus of the physical examination should be on elimination of the causes of delirium in the
cardiovascular, respiratory, abdominal, and neurologic systems. A rectal examination for fecal impaction is warranted if
the last bowel movement is not documented or it has been longer than 2 days since the last bowel movement.
Ancillary testing
Ancillary testing should include a complete blood count with differential, urinalysis, electrolyte testing, and
electrocardiography (ECG) for all patients. Additional laboratory and radiology studies can be ordered as appropriate
from the history and physical findings. The presence of an intracranial process without focal neurologic signs is rare and
the value of a noncontrast computed tomography (CT) scan of the brain is of limited value,[27] unless the history or
physical examination suggests an acute neurologic process.
Treatment of delirium
The primary treatment of delirium is prompt identification and management of the underlying causes. Because the cause
of delirium is likely to be multifactorial, multiple interventions must be started simultaneously. In addition, the medication
list should be reviewed and all medically unnecessary medications eliminated. Specific focus should be on eliminating
medications that were initiated immediately prior to the development of delirium, especially those with potential cognitive
side effects. If a medication cannot be eliminated entirely, its dose should be reduced or a less toxic alternative substituted.
History, physical examination, and laboratory and diagnostic studies should guide other simultaneous treatments.
Environmental changes should be used to maximize orientation, sensory input, and the sleep-wake cycle. Because the
delirious patient is residing in an environment different than his or her usual setting, with unrecognizable staff, repeated
reorientation can make the environment less foreign. Although a single reorientation may not have a significant impact,
repeated reorientation by all staff members can result in improvement.[26] The use of clocks, calendars, and message
boards can also provide reorienting stimuli.[26] Staff education on the assessment, prevention, and treatment of delirium
has been shown to reduce its duration, length of stay, and mortality.[28] As noted earlier, improving sensory input to the
brain though simple interventions such as the use of eyeglasses, hearing aids, and/or amplifiers can increase
environmental cues and assist in adaptation to the new environment.[26] Additional cues can provide reorienting stimuli,
such as increasing daytime stimulation by opening window shades and turning lights on. Conversely, decreasing nighttime
interruptions and turning lights off can provide environmental cues that night has arrived, promoting sleep. Ambulation of
the delirious patient is another way to provide orienting stimuli and represents constructive use of patient energy in the
hospital setting.
Removing unnecessary medical devices is an important treatment for delirium. The use of formal restraints has been
associated with delirium.[16] Moreover, informal restraints, such as intravenous catheters, oxygen tubing, urinary catheters,
and ECG leads, can confine patients to their bed. Although their use may be well meaning, these devices often lead to
complete bed rest, and can serve as a nidus for delirium, infection, or both. Limiting such factors can improve mobility
and delirium.
Management of agitation
It is important to recognize that treatment of agitation is not synonymous with treatment of delirium. In fact, managing
symptomatic agitation may prolong the course of delirium. Models of care exist in which patients are treated and
symptoms are managed in a physical and medication restraint-free environment without an increase in length of stay or
cost.[29] Only when nonpharmacologic management strategies have failed and agitated symptoms present a risk to the
patient should chemical restraint with medications be attempted. The goals of therapy and potential risks should be
considered prior to initiating therapy. Because of altered drug metabolism and body composition changes, older patients
have a narrow therapeutic window for drug therapy. Dosing should begin at the lowest possible dosage and advance
slowly.
Haloperidol is the drug of choice for the initial treatment of psychosis symptoms associated with delirium. Initial dosing
should be 0.25 to 0.50 mg intravenously or orally. Dosages may be increased slowly but should not exceed 5 mg/24 hours
in the older patient. Older patients are sensitive to antipsychotics and should be monitored for QTc interval prolongation
and extrapyramidal, anticholinergic, and parkinsonian side effects. Once symptoms have been controlled, the drug should
be tapered as soon as possible.
Newer atypical antipsychotic medications (e.g., olanzapine, quetiapine, risperidone, ziprasidone) theoretically have a less
toxic side effect profile in older patients. However, studies examining the effectiveness of atypical antipscychotics in
older patients have been limited in size and generalizability.[30] In a recent study of an older outpatient population with
dementia, short-term use (10 to 12 weeks) of atypical antipsychotics was associated with an increased risk of death[31]
compared with placebo. However, compared with conventional antipsychotics, atypical antipsychotics have a reduced risk
of death.[32] Although none of these studies directly pertain to the short-term use of these agents for delirium, the results
do emphasize the importance of minimizing medications to manage the agitation associated with delirium. Because
delirious patients are already at increased risk of death, the provider must carefully consider the risk-benefit ratio of using
this class of medications in these patients.
Benzodiazepines can cause or worsen delirium.[16] However, the management of refractory agitation requires the use of
medications with sedative activity. Lorazepam, starting at doses of 0.5 to 1.0 mg intravenously or orally, is recommended.
As with all medications, the dosage should be increased slowly and care should be taken to avoid oversedation because of
the risk of iatrogenic complications (e.g., pressure ulcers, aspiration pneumonia, falls). Also, older patients can have a
paradoxical reaction to benzodiazepines and become more agitated. Benzodiazepines are the treatment of choice in
Parkinson's disease and Lewy body dementia patients who cannot tolerate neuroleptics and for patients with delirium
associated with alcohol or sedative withdrawal.
Prevention of delirium
Over 50% of cases of delirium on an inpatient ward develop after the patient has been admitted, suggesting that there is an
iatrogenic cause of the delirium. Prevention strategies require identification of the predisposed population, minimizing
precipitating factors, appropriate prescribing of medication, surveillance for changes, and prompt assessment and
treatment when delirium develops.
A landmark study of delirium prevention was conducted by Inouye and associates at Yale-New Haven Hospital.[26] The
study used teams of “elder life specialists” who performed six delirium prevention interventions on patients on a medical
floor. The program was successful in reducing the incidence of delirium from 15.0% on a usual care floor to 9.9% in the
intervention group (adjusted OR, 0.60). Interventions included cognitive stimulation and reorientation, use of glasses and
hearing aids, ambulation three times a day, and a rehydration protocol. The intervention with the greatest impact was the
nonpharmacologic sleep protocol. For this bedtime protocol, sedative-hypnotics were delayed while the protocol was
implemented. Fluorescent lights were turned off and an incandescent nightlight was turned on. Patients were given warm
milk or herbal tea and a brief back massage, and relaxation tapes were played,. With this intervention, many patients fell
asleep spontaneously and the use of medication for sleep declined significantly.[33]
In another study of hip fracture patients, perioperative geriatric consultation was used as an intervention to prevent
postoperative delirium.[21] The geriatric consultants saw the patient prior to surgery or within 24 hours after surgery and
made recommendations in 10 module areas. The modules included adequate oxygen delivery, fluid and electrolyte
balance, pain management, regulation of bowel and bladder function, nutritional intake, early mobilization and
rehabilitation, prevention and early management of postoperative complications, improving sensory input, and treatment
of delirium. The surgical staff adherence to the recommendations of the geriatric consultants varied from 32%
(acetaminophen for pain) to 100% (deep venous thrombosis prophylaxis). The patients who received geriatric consultation
were less likely to develop delirium (32% versus 50%; P = .04) compared with usual care and were even less likely to
develop severe delirium (12% versus 29%; P = .02). In this study, geriatric consultation was able to prevent one case of
delirium for every 5.6 patients seen (RR = 0.64; 95% confidence interval [CI] 0.37 to 0.98). Although geriatric
consultation is not available in all institutions, the modules and recommendations in the study are evidence-based,
proactive, and practical geriatric interventions that can be carried out by hospitalists or other general medical consultants.
Conclusion
Health care providers play an important role in the optimal care of older patients. Because of the morbidity and mortality
associated with delirium, any change in a patient's mental status should be considered a medical emergency. Providers can
use history, physical, and ancillary testing to assess the multifactorial causes. Delirium is treated by the recognition and
treatment of the underlying causes. The management of agitation will not improve delirium and may prolong the course.
Finally, strategies to prevent delirium are effective and should be considered in the provider's practice, hospital, and health
care system.
Chapter 27 – Depression
Summary Points for the Primary Care Physician
•
Depression is common among older persons; however, it is not a part of normal aging.
•
The physician should have a high index of suspicion for depression in older persons, especially because many
of the features may be other than a depressed mood.
•
Ask about prior treatment for depression, because there may be a remitting or recurring pattern.
•
Patients who have unexplained somatic complaints should be carefully evaluated for depression.
•
Identifying a precipitant to the episode of depression does not mean that the episode should not be treated.
•
Medications concurrently prescribed with a selective serotonin reuptake inhibitor (SSRI) should be critically
reviewed to assess risk for precipitating a serious drug-drug interaction.
•
Psychotherapy is an effective component to the treatment of mild depression and also may complement the
medical management of depression.
•
Electroconvulsive therapy (ECT) is a safe and effective treatment for older persons with depression and
psychotic features.
•
It may be reasonable to reduce gradually and stop an antidepressant medication 12 months after remission but
dependent upon number and severity of previous episodes.
Practical Points for the Primary Care Physician
•
Older persons who are at high risk of suicide with an active plan may require police intervention for safe
transport to an emergency department for psychiatric evaluation.
•
Depression increases the morbidity and mortality for multiple common illnesses of older persons, including
myocardial infarction, stroke, diabetes, and cancer.
•
Older patients with persistent pain should be carefully evaluated and, as appropriate, treated for depression.
•
Depression may precede cognitive deficits in older adults by several years.
•
Older persons with depression who are making long-term permanent decisions should be carefully assessed
for their capacity to understand the implications of their decisions.
•
Key clinical features of the serotonin syndrome include confusion, agitation, autonomic dysfunction, and
muscle symptoms of tremor, hyper-reflexia, incoordination, and myoclonus.
As we shall summarize in this chapter, depressive conditions in later life are a major public health problem. They are
common and cause considerable distress and disability, but in most cases respond well to treatment. Most elderly patients
with depression do not see a psychiatrist or any mental health professional, but most do see their primary care physician or
geriatrician. Much of the responsibility for detection and management then rests on the training and skills of primary care
providers. Diagnostically, the diagnosis of depression in later life may be even more challenging, because the supposedly
cardinal symptom of depressed mood may be absent or less prominent than loss of enjoyment in life and other symptoms
such as anorexia, anergia, or insomnia.
Preliminary considerations
Epidemiology
Major depressive disorder has a point prevalence of approximately 1% to 2% in community-dwelling elderly, and 5% to
6% in older patients in a primary care setting. The prevalence is even higher in severely or chronically ill medical
populations and in institutional settings, including nursing home or rehabilitations units. [1] [2] Moreover, the prevalence of
so-called minor or subsyndromal depressive conditions—that is, clinically significant symptoms not meeting diagnostic
criteria for major depression (see later)—is higher than that for major depression alone. The increased rate of depression
in younger adult women (1.6 to 1.8 times that of younger adult men) decreases to some degree in older women
(approaching 1.1 to 1.2 times that of men). Bipolar disorder is an infrequent cause of depression in older patients, with a
point prevalence less than 1% in primary care, whereas new-onset primary (idiopathic) mania is rare in later life.
Consequences of illness and nontreatment
Geriatric depression is associated with morbidity and mortality. There appears to be a bidirectional relationship of effect
between the mood disorder and medical comorbidity. Depression is a potentially fatal disorder. In addition to suicide (see
later), depression also increases the risk of all-cause mortality.
Depression tends to recur, most often in a remitting-recurring pattern, although chronic continuous depression does occur.
The greater the number of previous depressive episodes, the more autonomous (i.e., not dependent on psychosocial
stressors) new episodes may become ( Fig. 27.1 ). This has led to speculation that “kindling” phenomena in the neuronal
circuits that mediate depression may contribute to the longitudinal course of illness, implying that multiple previous
episodes lower the stimulus needed for new ones to occur.
Fig. 27.1 Declining role for stressful life events with recurrent depressive episodes. *Odds ratio for at least one
stressful life event during month with a depressive episode. (Reprinted with permission from the American
Journal of Psychiatry. Copyright 2000, American Psychiatric Association.)
Pathogenesis
By definition, major depression is an idiopathic condition. However, there is considerable evidence supporting the roles of
a number of neurobiologic, psychological, and psychosocial factors in the pathogenesis of depression. Genetic factors
increase vulnerability to depression, although depression is polygenic and multifactorial in origin. Moreover, genetic
factors are less important in depression of older age of onset than in younger onset depressions, whereas acquired factors
play a greater role. Abnormal neurochemistry in depression includes alterations in the function of various neurotransmitter
systems, particularly norepinephrine and serotonin, and of other agents that serve as intracellular second messengers or
intercellular neuromodulators. Many depressed patients have increased activation of the hypothalamic-pituitary-adrenal
axis; over time, hypercortisolemia may produce neuronal cell death in the hippocampus, which may contribute to the
worsening course of depression and/or associated cognitive deficits. Psychological and psychosocial factors implicated in
depression include the emotional and cognitive processing of losses and the negotiation of role transitions or interpersonal
conflicts. Social isolation may contribute to and be caused by depression. Social networks and family relationships may
serve as buffers and/or stressors themselves, depending on the quantity and qualitative nature of these relationships.
Signs and symptoms
Major depression is a syndrome defined by diagnostic criteria, including depressed mood or loss of interest or pleasure in
activities (anhedonia), with a total of five symptoms in a 2-week period. It is important to note that most of the symptoms
must be present most of the day, nearly every day. The mnemonic SIG E CAPS (“prescribe energy capsules”) is helpful
for remembering the major categories of depression diagnosis:
Sleep—changes may manifest as insomnia or hypersomnia
Interest—loss of interest or pleasure, or depressed mood
Guilt—thoughts of guilt or worthlessness
Energy—loss of energy, fatigue
Concentration—diminished ability to concentrate or make decisions
Appetite—changes in appetite and weight
Psychomotor—psychomotor retardation or agitation
Suicide—suicidal thoughts, preoccupation with death, hopelessness
Another way to remember the symptoms of depression is to cluster them into groups:
•
Mood, emotional (depressed mood; anhedonia, apathy)
•
Cognitive, ideational (thoughts of worthlessness, helplessness, hopelessness, suicide)
•
Somatic, neurovegetative (decreased concentration and energy, altered sleep, appetite, or psychomotor activity,
diurnal or seasonal variation)
Elderly depressed patients may complain prominently about somatic symptoms, and may be less likely to report the
emotional or ideational components of their condition. Particularly common are physical symptoms such as headaches,
fatigue, disturbed sleep, dizziness, chest pain, vague joint or limb pain, vague back or abdominal pain, gastrointestinal (GI)
complaints (e.g., nausea, vomiting, constipation, diarrhea, gas), or sexual dysfunction.
Classification of depressive disorders in the elderly
In the elderly, two recognized subtypes of major depression are of particular importance. Major depression with
melancholic features is used to describe more severe depressions, defined by the presence of anhedonia or lack of
reactivity to pleasurable stimuli, and three or more of the following: distinct quality of depressed mood (experiences as
distinctly different from loss of a loved one), diurnal variation of mood, with mood regularly worse in the morning, early
morning awakening, marked psychomotor retardation or agitation, significant anorexia or weight loss, and excessive or
inappropriate guilt.[3] Melancholic unipolar depression is probably more common in older patients than in younger adults,
and has important implications for lack of responsiveness to psychosocial treatments alone (see later, “Treatment”). Major
depression with psychotic features includes psychotic symptoms, most commonly delusions (fixed false beliefs, often
about nihilistic, worthless, or other depression-congruent themes), although auditory or other hallucinations may occur.
Again, unipolar psychotic depression is more common in older than in younger patients. Psychotic depression requires
electroconvulsive therapy (ECT) or treatment with a combination of antipsychotic and antidepressant medications (see
later).
Dysthymic disorder is a long-recognized condition that includes chronic low-level depressive symptoms that are less
severe than those of major depression but nonetheless cause considerable distress or functional impairment. It has become
clear in recent years that a substantial proportion of older adults with clinically significant depressive symptoms do not
meet diagnostic criteria for major depression or dysthymic disorder. Various terms have been used for such conditions,
including minor depression, subsyndromal depression, and subthreshold depression, using several proposed diagnostic
criteria sets that await further empirical validation. The evidence base for treatment of these so-called lesser depressions is
more limited than for major depression. There have been some suggestions that they may be preferentially responsive to
psychosocial rather than somatic interventions.[4]
Differential diagnosis and evaluation
Many medical conditions present with symptoms that partially mimic those of idiopathic depressive disorders. For
example, there is the patient with a quiet delirium, whose withdrawal (caused by psychomotor slowing or internal
preoccupation with hallucinations) may be mistaken for depression. Sometimes, a medical condition may present with all
the signs and symptoms of a major depressive episode; if the depressive syndrome is caused by the underlying medical
condition or substance, it is known as a secondary depression. A partial list of such causes is provided in Table 27.1 .
Table 27.1 -- General medical conditions causing or contributing to major depression[*]
Causative factor(s)
Examples
Drugs and poisons
Alcohol, β-blockers, steroids, opiates, barbiturates, withdrawal from cocaine and
amphetamines, heavy-metal poisoning, cholinesterase inhibitors, cimetidine, chemotherapy
agents
Metabolic and endocrine
disorders
Hyper- and hypothyroidism, severe anemia, hyperparathyroidism, hypokalemia,
hyponatremia, Cushing's disease, Addison's disease, uremia, hypopituitarism, porphyria,
Wilson's disease, Wernicke-Korsakoff syndrome
Infectious diseases
Tuberculosis, Epstein-Barr infection, human immunodeficiency virus (HIV) infection,
pneumonia, postinfluenza, tertiary syphilis, encephalitis, postencephalitic states
Neurodegenerative and
demyelinating diseases
Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease
Causative factor(s)
Examples
Other neurologic disorders
Subdural hematoma, normal-pressure hydrocephalus, strokes, other traumatic brain injury,
cerebral tumors
Neoplasia
Carcinomatosis, cancers of the pancreas, lung, breast, others
Other disorders
Systemic lupus erythematosus, other collagen vascular disorders, other chronic
inflammatory or autoimmune disorders, congestive heart failure
*
Also referred to as secondary depression.
Having a precipitant to the depressive episode does not mean that the depression is explainable and therefore does not
need to be treated as a major depressive episode. The decision to treat should be made solely on the basis of meeting
criteria for a major depressive episode, whether or not an identifiable precipitant is present. A common differential
diagnosis that will present to the primary care physician or geriatrician would be distinguishing between major depression,
adjustment disorder with depressed mood, and bereavement ( Table 27.2 ). The first is an illness, the second is probably
an illness, and the third is considered a normal expected reaction to a life situation. Major depression is treated with
specific somatic treatments or psychotherapy. Sometimes, adjustment disorder, which also might be minor or
subsyndromal depression, is treated with medication, especially patients in whom an ongoing severe stressor is present.
However, most of these situations respond to a good listener and support. For bereavement, support is the major
intervention in addition to target symptom relief, such as treatment of insomnia, anorexia, or anxiety.
Table 27.2 -- Differential diagnosis: major depression and adjustment disorders with depressed mood or
bereavement
Adjustment disorder with depressed
Parameter Major depression
mood
Bereavement[*]
Distinction Illness
Probably an illness
Normal, expected reactions to life
situation
Symptoms
Multiple—mood, emotional; Few, does not meet major depressive
cognitive, ideational;
episode (MDE) criteria
somatic, neurovegetative
Duration
Persists
Onset within 3 mo; duration, 6 mo or less Less than 2 mo (generally)
Suicidal
potential
Can result in suicide
Rare suicidal ideation, but can occur
Usually no suicidal ideation
Treatment
Specific medical-psychiatric
treatment; somatic treatment,
with or without
psychotherapy, as indicated
Having a good listener and support of
others, time; brief symptomatic treatment
(e.g., sleep aid for insomnia,
benzodiazepine for anxiety);
antidepressants possibly, if ongoing
stressor
Having a good listener and
support of others, time; brief
symptomatic treatment (e.g., sleep
aid for insomnia, benzodiazepine
for anxiety)
*
Largely mood, sometimes
insomnia, anorexia, anxiety
Not bereavement but probably major depression if there is guilt about things other than actions taken or not taken by
survivor; suicidal ideation; morbid preoccupation with worthlessness; marked psychomotor retardation; prolonged and
marked functional impairment; hallucinations (other than transient) of the deceased person.
Bipolar disorders, although less common in the elderly than major depression, are typically seen within the spectrum of
bipolar I (mania alternating with major depressive episodes), bipolar II (hypomania alternating with major depressive
episodes), cyclothymia (hypomania alternating with depressive symptoms that do not meet criteria for major depressive
episode), bipolar disorder, not otherwise specified (NOS; have bipolar features that do not meet criteria for any of the
aforementioned bipolar disorders). Given that antidepressants may induce mania, it is important to consider whether the
depressive episode that is being evaluated is not the depressive phase of a bipolar disorder before treating with an
antidepressant in the absence of a mood stabilizer.
Practical recommendations for evaluation
The clinician should determine the thyroid-stimulating hormone (TSH) level if a thyroid disorder is suspected or other
testing and physical examination be carried out as appropriate and per clinical suspicion. The patient should be monitored
for suicidal ideation, homicidal tendencies, and psychotic manifestations, such as auditory or visual hallucinations or
paranoia. Psychotic ideation may greatly affect the safety evaluation, depending on the degree to which the patient
believes their altered thinking. A family history of depression in the patient is useful as an external validator of the illness.
However, as the person ages, he or she may or may not remember as much about their past or family history. Also, any
cognitive distortions or motivational issues that may affect the person's compliance should be assessed.
When to refer
Psychiatric referral should be considered in the following circumstances:
•
More severe symptomatology
•
Suicidal tendencies
•
Bipolar disorder that is unstable
•
Atypical depression
•
Psychotic depression
•
Treatment-resistant depression
•
Treatment-intolerant depression
•
Complicated drug-drug interactions
•
Patient preference for psychiatric referral or counseling
•
Diagnostic uncertainty
Treatment
Table 27.3 -- Treatment phases of depression
Phase
Goal
Duration
Acute phase
The goal is to get a response and then full alleviation of symptoms (i.e., remission).
6-12 wk
Continuation
phase
This is the phase after full remission has been achieved. The goal is to keep well for 4-9 wk
long enough to have treated the episode completely (i.e., to promote recovery and
prevent relapse).
Maintenance
phase
After the patient has recovered from the acute episode of depression, the goal is to
prevent further recurrences.
1 yr or longer, or
indefinitely
Recovery, remission long enough to treat the episode through the continuation phase; recurrence, return of symptoms after
recovery (i.e., a new episode); relapse, return of symptoms after response or remission; remission, full resolution of
symptoms; response, 50% or more reduction of symptoms.
Acute phase
Pharmacotherapy
Antidepressant medications are marketed after they have successfully produced a 50% or greater reduction of symptom
response compared with placebo. However, remission is the emerging treatment standard for improved quality of life as
well as for best practice, because those who do not achieve remission have a four- to fivefold chance of recurrence of their
depression compared with those who have achieved remission ( Fig. 27.2 ).[5] Early and aggressive intervention also is
important, because patients without full remission within 3 months of initiating treatment tend to have a much higher risk
of relapse of symptoms.[6]
Fig. 27.2 Longitudinal follow-up study of patients treated with usual care by their physicians. Shown here is
response versus remission and the risk of relapse. *P <.001 between treatment groups. (From Paykel ES,
Ramana R, Cooper Z, et al: Residual symptoms after partial remission: An important outcome in depression.
Psychol Med 1995;25:1171-1180.)
Medication choices
Table 27.4 presents distinguishing characteristics of various classes of antidepressants. In general, SSRI antidepressants
are the most common and easy to use medications for treatment of depression.
Table 27.4 -- Characteristics of antidepressants
Class
Name
Comments
Tricyclic
Desipramine
(Norpramin)
Most noradrenergic and least anticholinergic of tricyclics; therapeutic levels
meaningful
Nortriptyline
(Pamelor, Aventyl)
Almost the least anticholinergic of tricyclics; probably the least likely to induce
orthostatic hypotension; therapeutic window is such that serum levels above or
below therapeutic are less effective
SNRI
SSRI
Venlafaxine (Effexor) Efficacy in severe depression, SSRI failures; few drug-drug interactions, better
remission rate over pooled SSRI data; dual reuptake inhibition
Duloxetine
(Cymbalta)
Dual reuptake inhibition, even at lowest doses; alternative in poor responders to
SSRIs; useful in MDD with comorbid pain syndrome.
Fluoxetine (Prozac)
Longer half-life than other antidepressants; little to no discontinuation syndrome
risk; well studied; weekly formulation available
Sertraline (Zoloft)
Few drug-drug interactions; large medical and geriatric experience; efficacious for
severe depression.
Paroxetine (Paxil)
Efficacy shown for various anxiety disorders
Citalopram (Celexa)
Few drug-drug interactions; large primary care and geriatric experience in Europe;
appears to have early anxiolytic response
Escitalopram
(Lexapro)
S stereoisomer of citalopram; possibly fewer side effects and more efficacious than
citalopram
Fluvoxamine (Luvox) Used as antidepressant in Europe; marketed in United States for obsessivecompulsive disorder
5-HT2
antagonist
Trazodone (Desyrel)
Mostly off-label use as sedative-hypnotic
Nefazodone
Used for anxious depression; improves sleep; few sexual side effects;
hepatotoxicity risk of concern
DNRI
Bupropion
(Wellbutrin, Zyban)
Few sexual or GI side effects; beneficial geriatric profile; may help addictions
MAOI
Tranylcypromine
(Parnate)
Avoid foods with tyramine (e.g., cheese), sympathomimetics, which may cause
hypertensive reaction; more activing of MAOIs (helpful for patients who are
slowed with poor energy, drive, etc.)
Phenelzine (Nardil)
Avoid foods with tyramine (e.g., cheese), sympathomimetics, which may cause
hypertensive reaction; known for anxiolytic benefit among MAOIs
Mirtazapine
(Remeron)
Beneficial for agitated refractory patients; few sexual and GI side effects; improves
sleep; few drug-drug interactions; SolTab formulation available
NaSSA
5-HT2 antagonist, postsynaptic serotonin 2 receptor antagonist; DNRI, dopamine-norepinephrine reuptake inhibitor;
MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; NaSSA, norepinephrine and specific serotonin
antidepressant; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; tricyclic,
tricyclic antidepressant.
Although all available antidepressants have been shown to be effective in antidepressant response, understanding the
association of mood-regulating neurotransmitters may assist in the initial choice of antidepressant and for patients in
whom specific residual symptoms continue despite the antidepressant trial ( Fig. 27.3 ). The following are classes of
antidepressants:
TCA—tricyclic antidepressant
SNRI—serotonin-norepinephrine reuptake inhibitor
SSRI—selective serotonin reuptake inhibitor
5-HT2 antagonist—5-HT(serotonin)2 postsynaptic receptor antagonist
DNRI—dopamine-norepinephrine reuptake inhibitor
MAOI—monoamine oxidase inhibitor
NaSSA—norepinephrine and specific serotonin antidepressant (causes enhanced release of serotonin and
norepinephrine release by presynaptic α2-blockade, as well as blocking 5-HT2 and 5-HT3 serotonin receptors,
postsynaptically).
Fig. 27.3 Common neurotransmitters involved in regulating mood.
SSRIs are popular for the treatment of depression, but some are strong metabolic inhibitors ( Table 27.5 ) of certain
cytochrome P450 substrates ( Table 27.6 ). The elderly are frequently on numerous medications, so this potential for
interaction becomes a highly relevant clinical issue. The risk of drug-drug interactions with certain SSRIs is profound
(e.g., more than a three- or fourfold elevation of substrate), whereas with others it is clinically insignificant. Medications
coprescribed with an antidepressant that have a narrow therapeutic window, such as β-blockers and warfarin, may have
devastating consequences if the potential for impaired metabolism is not considered and dose adjustments made.
Table 27.5 -- Cytochrome P450 enzyme inhibition
Cytochrome P450 substrates
Drug
3A4
2D6 2C19 2C9 2A6 1A2
Desipramine (Norpramine)
0
XX?
0
0
0
0
Nortriptyline (Pamelor, Aventyl)
0
0
0
0
0
0
Venlafaxine (Effexor)
0
X
0
0
0
0
Duloxetine (Cymbalta)
0
XX
0?
0
0
0/X
0
X
Fluoxetine (Prozac)
XX XXX XX XX
Sertraline (Zoloft)
X
X
XX
X
0
X
Paroxetine (Paxil)
X
XXX
X
X
0
X
Citalopram (Celexa)
0
X
0
0
0
X
Escitalopram (Lexapro)
0
0
0
0
0
0
Fluvoxamine (Luvox)
XXX
0
XXX
0
0
XXX
Trazadone (Desyrel)
0
0
0
0
0
0
XXX
0
0
0
0
0
Buproprion (Wellbutrin, Zyban)
0
XXX
0
0
0
0
Tranylcypromine (Parnate)
0
0
XX?
0
XX?
0
Phenelzine (Nardil)
?
?
?
?
?
?
Mirtazapine (Remeron)
X
X
0
0
0
0
Nefazadone (Serzone)
0, None; X, low; XX, moderate; XXX, strong; ?, unknown or unclear degree.
Table 27.6 -- Drug interactions: cytochrome P450 substrate metabolic pathways
3A4
3A4
2D6
2C19
2C9
2A6
Dextromethorphan
Diltiazem
Codeine
Lansoprazole
Diclofenac
Ac
Erythromycin
Nifedipine
Dextromethorphan
Omeprazole
Ibuprofen
De
Haloperidol
Verapamil
Desipramine
Pantoprazole
Naproxen
Le
Imipramine
Indinavir
Nortriptyline
Rabeprazole
Piroxicam
Mo
Methadone
Nelfinavir
Fluoxetine
Citalopram
Tolbutamide
Nic
Prednisone
Ritonavir
Paroxetine
Diazepam
Amitriptyline
Rit
Sertraline
Saquinavir
Fluvoxamine
Imipramine
Celecoxib
To
Tamoxifen
Carbamazepine
Venlafaxine
Mephenytoin
Fluoxetine
Alprazolam
Cisapride
Propranolol
R-Warfarin
Phenytoin
Diazepam
Citalopram
Metoprolol
Sulfamethoxazole
Midazolam
Clomipramine
Timolol
Tamoxifen
Triazolam
Clonazepam
Perphenazine
S-Warfarin
Cyclobenzaprine
Risperidone
Cyclosporine
Thioridazine
Tamoxifen
Tramadol
Duloxetine
Drug-drug interactions: Case vignettes
1. A 65-year-old man with hypertension has been treated with a β-blocker, propranolol. His blood pressure was in
good range and his pulse was about 60 to 62 beats/min. After becoming clinically depressed, fluoxetine was
chosen as the antidepressant. Two to 3 weeks later, the patient came to the emergency department with a heart rate
of 40 beats/min. It was determined that an interaction had occurred between the patient's fluoxetine and
propranolol. This increased his serum level of propranolol to the point of reducing his heart rate, despite receiving
the same oral dose of β-blocker that he had been on prior to fluoxetine.
2.
A 76-year-old female with a history of stroke is on warfarin and has been running a therapeutic international
normalized ratio (INR). She became depressed and paroxetine was added. One to 2 weeks later, the patient comes
to the emergency department with a GI bleed. It was determined that the patient's INR was highly elevated
because of an elevation of her serum warfarin level caused by interaction with paroxetine.
In summary, antidepressants that interact with other drugs can be used carefully but will need to be watched much more
closely, because interactions need to be anticipated and substrate medications adjusted appropriately.
Psychotherapy
Psychotherapy can be just as effective as antidepressants, especially in mild to moderate depression. Interpersonal
psychotherapy (IPT), cognitive-behavioral therapy (CBT), and problem-solving treatment (PST) have been shown to be
very effective and are treatment alternatives guided by patient choice in mild to moderate depression. However, finding an
appropriate, sufficiently trained mental health professional to administer these methods of psychotherapy may be a
challenge, depending on the community resources available.
Patient choice will often guide whether psychotherapy or pharmacotherapy should be tried. However, those with severe
depression will not respond to psychotherapy alone and will need somatic treatment as well.
Light therapy
Light therapy has been found to be highly effective in depression with a seasonal pattern of the winter depression type.
Light therapy has also been useful in nonseasonal depression, although it may take somewhat longer to work—for
example, 3 to 4 weeks compared with the 4-day onset of response typical in seasonal depression.
Electroconvulsive therapy
Electroconvulsive therapy (ECT) is a first-line treatment for depression with psychotic features; it is an alternative to
combination medication treatment with antidepressants and antipsychotics. An acute series of ECT (e.g., three times/week
for 2 to 4 weeks) may also be a reasonable choice for new episodes of major depression if there is a known previous
response to ECT. It is the most effective treatment known for depression, with response rates of 80% to 90%. It also may
be lifesaving in those patients with catatonia, who are not eating or drinking, or who are highly suicidal. Mania is
responsive to ECT; this should be a consideration because of the physical toll that persistent mania might have on an older
adult.
Maintenance ECT is the use of specifically timed ECT treatments as often as once weekly to once a month. This can be
the sole or adjunctive treatment needed to achieve ongoing sustained remission during continuation and/or maintenance
phases of treatment.
Overall, ECT is a safe and effective procedure for the elderly; the most commonly reported side effects are impaired
memory (14%), confusion (6%), and hypertension (6%).[7] ECT can cause a significant increase in bigeminy, trigeminy,
and supraventricular tachycardia, but other arrhythmias are not increased. The clinical significance of these arrhythmias is
not clear, although pre-ECT arrhythmias have correlated well with post-ECT arrhythmias.[8] Another complication of ECT
in the elderly is the risk for falls, which increases with the number of treatments given and with comorbid conditions such
as Parkinson's disease.[9]
Newer somatic therapies
Repetitive transcranial magnetic stimulation (rTMS) is being studied as an alternative to ECT but is not as effective as
ECT for psychotic depression. It might have more benefit in nonpsychotic depression than ECT, because general
anesthesia is not needed and there is less impairment of memory. However, further studies will be needed to elucidate this
issue.
Vagal nerve stimulation (VNS) is being studied for treatment-resistant depression. The surgically implanted device
delivers a stimulus at various intervals to the vagus nerve. One drawback is the effect on voice during stimulation phases,
but the device can be turned off as needed.
Herbal remedies and precursors
Herbal remedies are often used by patients, sometimes without the physician's knowledge. St. John's wort, for example, is
a hepatic enzyme inducer and may actually reduce the drug level of other substrates, such as antiretroviral drugs, lidocaine,
calcium channel blockers, midazolam, and cyclosporine. Other herbals may be metabolic inhibitors. Therefore, it is
important to try to determine whether over-the-counter remedies are used by those who are depressed, because patients
may unknowingly consider them benign. However, they may negatively affect the treatment of concomitant conditions.
Precursors to neurotransmitters are sometimes used as supplements, such as l-phenylalanine or l-tyrosine. These amino
acids are precursors in the synthesis of the neurotransmitters norepinephrine and dopamine. Increased dietary amounts
through supplementation are thought to enhance the neurotransmitter production of norepinephrine and dopamine by
increasing the quantity of substrate required for synthesis.
Continuation phase
Medication needs to be continued after the acute phase remission to treat the depressive episode successfully. For the first
major depressive episode, the Agency for Health Care Policy and Reform (AHCPR) guidelines [10] for the treatment of
depression in primary care suggest treatment of the depressive episode for at least 4 to 9 months after remission before
medication is gradually reduced and discontinued. However, the geriatrician is faced with a more complicated clinical
decision, because first-episode depressions in the elderly recur more often than in younger patients.
Maintenance phase
To stay well, many patients may need indefinite maintenance treatment after the continuation phase. The recurrence rate
within 5 years of recovery from the previous episode is approximately 50% after the first episode, 70% after the second,
and more than 90% after the third. Therefore, those patients with three or more previous episodes clearly require
maintenance treatment, or a patient's personal choice to remain on maintenance medication at any point should be heeded
( Fig. 27.4 ). Severe psychosis and suicidal ideation during the index depressive episode are factored into the clinical
decision to have the patient stay on medications beyond the continuation phase. Those with an older age of onset have a
higher risk of recurrence in the ensuing period than those with a younger age of onset ( Fig. 27.5 ). The effects on
comorbid medical conditions are considered in maintenance decisions, because a person's comorbid medical condition
may be affected adversely if another episode of depression were to occur.
Fig. 27.4 Relationship between cycle length and episode number. (From Goodwin FK, Jamison KR: In
Goodwin FK, Jamison KR: Manic-Depressive Illness. New York, Oxford University Press, 1990, pp 127-156.)
Fig. 27.5 Probability of a relapse within 24 months following the initial episode of depression. (From Zis AP,
Grof P, Webster M, Goodwin FK: Prediction of relapse in recurrent affective disorder. Psychopharmacol Bull
1980;16:47-49.)
Suicide risk in the elderly
When a depressed patient is identified, assessment of suicide risk is essential. U.S. mortality statistics have shown that
approximately 19% of suicides are committed by those 65 years of age or older. Most elderly persons who committed
suicide visited their physician in the month prior to their death.[11] Given such a high likelihood of an office visit prior to
suicide, the primary care physician and geriatrician have the unique opportunity to intervene. It is important to ask
whether the patient has thoughts of death or suicide or think that life is not worth living. If she or he answers “yes,” it is
important to determine whether there is a specific plan for carrying out the suicide. Variables associated with high risk of
suicide include previous suicide attempts, family history of suicide, comorbid substance abuse, advanced age, male gender,
white race, comorbid medical illness, psychosis, living alone, and feelings of hopelessness.
If the patient has suicidal ideation but does not have an active plan, aggressive depression treatment is important in
assessing suicide risk at each visit; visits should be closer together than for those without suicidal ideation. Patients with
tenuous suicidal ideation should have psychiatric referral promptly. Those with a suicide plan should have immediate
psychiatric consultation, with consideration of transporting the patient to the psychiatric emergency department. Because
cognitive distortions may play a role in severe depression, the physician might not be able to elicit the cooperation of the
patient to get help, because the patient's hopelessness may be pervasive. In such cases, the police may need to be called
for a mental hygiene arrest to give the patient safe transport to the emergency department for a psychiatric evaluation,
even if it is against the patient's wishes. State laws typically recognize the existence of cognitive distortions that are a
temporary condition caused by the psychiatric illness, and are not necessarily the lifelong and rational wishes of a patient
who would otherwise have the right to liberty guaranteed by the Constitution. Although contracting for safety with the
patient may be somewhat helpful, it is not always effective in preventing suicidal acts and is usually not protective in
malpractice cases.[12]
Effects of depression on morbidity and mortality
After myocardial infarction (MI), depression may worsen morbidity and mortality. [13] [14] Safe treatment of depression
post-MI is a focus of much research. There has been some early work on the safe use of sertraline post-MI in helping
reduce risks of depression on the patient.[15]
Depression increases morbidity and mortality in congestive heart failure. [16] [17] Depression increases the risk of mortality
of patients in nursing homes.[18] Depression worsens morbidity poststroke,[19] and depression may worsen the outcomes of
cancer, diabetes, AIDS, and other disorders.[20] The effects of depression treatments on the outcome of the comorbid
medical condition are now being studied.
Treatment-resistant depression
Treatment-resistant depression (TRD) is common. Thirty percent of patients do not respond to antidepressant therapy.
Fewer than 35% achieve full remission.[21]
Standardized definitions for TRD are being developed, but the most commonly referred to staging system was that
proposed by Thase and Rush in 1997[22]:
Level I—Failure of at least one adequate trial of one major class of antidepressant
Level II—stage I resistance plus failure of an adequate trial of antidepressant from a different class
Level III—stage II plus failure of a TCA
Level IV—stage III plus failure of an MAOI
Level V—stage IV plus failure of bilateral ECT
TRD has been shown to increase costs involved in the general medical care of the patient,[23] in addition to the high degree
of morbidity affecting the patient's quality of life and ability to function. The geriatrician should consider referral to a
psychiatrist when treatment-resistant depression is identified, unless the patient strongly opposes the referral.
Special topics
Cerebrovascular model of depression
Evidence from neuropsychological and neuroimaging investigations, together with epidemiologic studies of risk factors,
support the notion that some depressive conditions in later life are caused, precipitated, or perpetuated by otherwise
clinically occult small vessel cerebrovascular disease.[24] Currently, there is little evidence that different treatment
strategies are required for this so-called vascular depression, although it is tempting to speculate that optimal long-term
management of cerebrovascular risk factors (e.g., hypertension, diabetes mellitus, cigarette smoking) in younger and
middle-aged adults may prevent some types of depression in their later years.
Depression and pain
The descending tracts in the spinal cord are the proposed mechanism of amplification of pain when a patient is depressed.
The treatment of depression is essential for pain patients and the clinician should be vigilant for an evolving depression
caused by chronic pain. Although many antidepressants have been studied, it appears that those with a dual
neurotransmitter action (serotonin and norepinephrine) are associated with a better response as an adjunctive medication
in pain relief control than those with a single neurotransmitter effect. Dual-action medications include the tricyclic
antidepressants venlafaxine (Effexor), mirtazapine (Remeron), and duloxetine (Cymbalta). However, their adverse side
effects should also be considered (see Tables 27.5 and 27.6 [5] [6]).
Depression and dementia
Depressive symptoms and syndromes are commonly manifested during the course of dementia caused by neurologic
disease, including Alzheimer's disease and vascular dementia. Aggressive treatment of depression can substantially
improve functioning and quality of life in such patients. However, the prognosis for full and sustained remission of the
depression is poorer, as is true in the presence of many medical comorbidities, than for depression in the absence of such
comorbidity. Because of difficulties in symptom overlap with dementia, provisional diagnostic criteria for depression in
Alzheimer's disease have been proposed.[25] These criteria require the presence of 3 of 11 symptoms; the list includes the
usual symptoms of major depression, with the addition of social withdrawal or irritability.
Conversely, severe depressive episodes may present with profound functional impairment and cognitive complaints. As
recently as the 1980s, these presentations were commonly mistakenly diagnosed as dementia; the popularization of the
term pseudodementia and widespread education efforts have reduced the prevalence of such misdiagnoses. However,
empirical research has demonstrated that some older patients with severe idiopathic major depression may have actual
cognitive deficits that usually resolve with the remission of their depression, a condition that has become known as
dementia of depression. Growing evidence suggests that these patients are at higher risk of developing a
neurodegenerative dementia within several years of the original depressive episode. Some studies have focused on the role
of a specific type of cognitive deficit, so-called “executive dysfunction.” Executive functions include tasks such as
initiating, organizing, sequencing, and planning, which are substantially mediated by the frontal lobes. Patients with
depression and prominent executive dysfunction may have particularly poor overall functional status or prognosis, which
has led some to propose that a depression-executive dysfunction syndrome in later life may be of heuristic value.[26]
Depression affecting capacity to make decisions and end-of-life issues
Because depression may affect the cognitive triad of how patients view themselves, the world, and the future, the impact
of depression on making long-term and final decisions is of utmost clinical concern. Conversely, however, having a
depressive episode is not always sufficient to impair judgment and the ability to make rational decisions. Most studies
have suggested that those with moderate to severe depression may be more likely to have their capacity to make decisions
affected than those with mild forms of depression Therefore, in patients with moderate to severe depression, the ability to
make long-term permanent decisions should be assessed in the context of whether the patient can understand the
implication(s) of his or her decisions.
To assess capacity, clinicians must determine whether the patient demonstrates the following four key components [27]: (1)
understanding the illness in question, its outcomes, and treatment options; (2) appreciation of the significance and
implications of these facts; (3) reasoned consideration of the decision to be made, in keeping with personal and cultural
preferences and values; and (4) an expressed choice, stated clearly and consistently.
Syndromes associated with antidepressants
Serotonin syndrome
Many medications, especially the antidepressants, have the potential to affect the serotonin system. Combining various
medications may risk the development of serotonin syndrome (SS), which can have a number of effects:
Cognitive and behavioral effects—confusion, hypomania, agitation
Autonomic dysfunction effects—diarrhea, shivering, fever, diaphoresis, variable effects on blood pressure, nausea
and vomiting.
Neuromuscular effects—myoclonus, hyper-reflexia, incoordination, and tremor
SS may mimic some of the signs and symptoms of neuroleptic malignant syndrome (NMS). Distinguishing features of
NMS are tachycardia, a marked increase in the levels of creatine phosphokinase (CPK) and white blood cells (WBCs),
and tachypnea. Usually, discontinuation of the offending serotonergic agent leads to resolution of the symptoms of
serotonin syndrome within 24 hours.
SSRI discontinuation syndrome
In patients who are poorly or intermittently compliant, discontinue their antidepressant on their own, or are hospitalized
for another reason and their antidepressant is discontinued, SSRI discontinuation syndrome may develop. Often,
symptoms peak 2 to 4 days after discontinuation of the medications or after dosage is reduced. This syndrome may mimic
the signs and symptoms of the original illness of depression or anxiety, but is often fraught with severe irritability,
nightmares, and occasionally autonomic instability.
A useful mnemonic to remember the effects of this syndrome is AMINES:
Adrenergic excess symptoms
Mood and anxiety fluctuations, confusion, disorientation
Intestinal flulike illness, hypotension
Extrapyramidal symptoms, akathisia, dyskinesia, dystonia, paresthesias, and shocklike sensations
Sleep disturbances, nightmares
Discontinuation syndrome can be differentiated from a relapse or recurrence of depression by reinstituting the
discontinued medication, which should improve symptoms within hours compared with the usual time needed to improve
symptoms of a new episode of depression. In older adults who have memory problems and complain of severe anxiety
acutely, the physician should consider the possibility that they may be falsely conveying compliance to their medication
regimen. Accurate compliance history, when possible, is important in this diagnosis.
If, for medical reasons, the patient cannot be reinstituted on the SSRI, drugs with anticholinergic or anxiolytic properties
may help the patient through the worst times, which typically may be up to about 2 weeks.