Psychosis in Elderly Patients:

Classification and Pharmacotherapy

Jacobo Mintzer, MD, and Steven D. Targum, MD

ABSTRACT

Psychosis in elderly patients is a growing clinical concern because psychotic symptoms most frequently occur as noncog-
nitive manifestations of Alzheimer’s disease, as side effects of drug therapy for Parkinson’s disease, or as the primary
abnormalities in schizophrenia, and the clinical characteristics of psychosis are distinct for each. In planning antipsy-
chotic pharmacotherapy for elderly patients, age-related pharmacokinetic changes, polypharmacy for comorbid diseases,
and concerns about the underlying conditions responsible for the psychotic symptoms must be considered. Traditional
antipsychotic agents bind to dopamine receptors and effectively relieve positive schizophrenic symptoms but frequently
cause tardive dyskinesia and other extrapyramidal symptoms, a problem for elderly patients, particularly for those
with Parkinson’s disease. Atypical antipsychotics bind to dopamine and serotonin receptors, relieving both positive and
negative symptoms, and are less likely to cause extrapyramidal symptoms. The authors review common diagnostics
associated with psychosis in the elderly and clinical guidelines to selecting antipsychotic pharmacotherapy. (J Geriatr
Psychiatry Neurol 2003; 16:199-206)

Keywords: psychosis; elderly; pharmacotherapy; atypical antipsychotics

Psychosis is characterized by hallucinations or delusions
that are not attributable to other causes, such as intoxi-
cation or delirium. Among elderly patients, psychosis is
encountered mainly in association with Alzheimer’s dis-
ease (AD), Parkinson’s disease (PD), and schizophrenia. Psy-
chosis may be associated with aggressive or disruptive
1 2,3
behavior, often causing distress to caregivers, which may
result in the neglect or abuse of patients or costly insti-
4-8
tutionalization. The institutionalization of the elderly is
more often prompted by psychosis than by the dementia
associated with AD or the motor deficits associated with
PD.9-11 Psychotic disorders are reported in < 5% of
community-based elderly patients in the United States,
compared to 10% to 63% of elderly patients in nursing
12
homes.
The elderly account for 12% of the US population,
13
and that figure is expected to rise to 20% by 2030. There-
fore, psychosis in the elderly is a large and growing con-
cern. This article reviews the clinical conditions in which
psychosis most frequently occurs in elderly patients, with
emphasis on current concepts relating to the pathology and
classification of psychotic disorders in elderly patients
and appropriate antipsychotic pharmacotherapy in this
population.
CLASSIFICATION AND
CLINICAL PRESENTATION

The causes and clinical manifestations of psychosis in

From the Medical University of South Carolina, Institute of Psychiatry,
Charleston (Dr Mintzer); and Clinical Studies Ltd (Dr Targum).
The work described in this article was conducted at the Medical University
of South Carolina as part of the Alzheimer’s Research and Clinical
Programs. Support for this work was provided by AstraZeneca. Excerpts
of this work have not been presented.
Address correspondence to Jacobo Mintzer, MD, Medical University of
South Carolina, Institute of Psychiatry (PH-141), 67 President Street,
PO Box 250861, Charleston, SC 29406; e-mail: mintzerj@musc.edu.
DOI: 10.1177/0891988703258658
elderly patients vary with the underlying condition. In
patients with AD, psychosis is a noncognitive condition that
often accompanies dementia. In patients with PD, treat-
ment with antiparkinsonian drugs is the most frequent
cause of psychotic symptoms. In patients with schizo-
phrenia, psychosis is the primary expression of the disor-
der. Although the focus of this article is on psychosis in
elderly patients with AD, PD, and schizophrenia, other diag-
noses associated with psychosis in the elderly include
delirium, delusional disorder, mood disorder, substance

© 2003 Sage Publications 199

200 Journal of Geriatric Psychiatry and Neurology / Vol. 16, No. 4, December 2003
abuse, chronic medical conditions, and drug-induced (other
14
than dopamine) psychosis.
Alzheimer’s Disease
The incidence of AD rises with age, and AD currently
15
affects 7% of the population aged 65 and over. As the pop-
ulation ages, the prevalence of AD is expected to more than
triple by 2050, from the current 4 million to approximately
16
14 million. Similarly, the annual incidence is expected to
more than double, from an estimated 377,000 new cases
17
in 1995 to almost 1 million new cases per year by 2050.
Psychosis is among the most prominent of the noncog-
nitive symptoms encountered in patients with AD. The
prevalence of psychosis in patients with AD has been esti-
16
mated at 30% to 50%. In a community-based study of
patients with presumed AD, one third showed evidence of
psychosis, with delusions reported more often than hal-
18
lucinations. Other published studies have reported com-
parable prevalence rates of delusions and/or hallucinations
in patients with AD.19-21 Complementing these findings, a
study of 329 patients with AD but no psychosis at base-
line showed that half of them developed psychotic symp-
22
toms within 4 years.
It is uncertain, however, whether all the delusions
reported in patients with AD are true psychotic delusions
or consequences of cognitive deficits. For example, AD
patients who fail to recognize their family members and
homes may become convinced that they are in the hands
of strangers, in strange environments. In individual
patients, it is a matter of clinical judgment as to whether
such false beliefs should be considered delusions or the
effects of amnesia and agnosia.
In patients with AD, psychosis is now considered a pri-
mary manifestation of the underlying pathology rather than
a secondary manifestation of dementia, as reflected in the
current classification of psychotic symptoms in this pop-
ulation. The categories previously listed as AD “with delir-
ium,” “with delusions,” and “with depressed mood” have
been eliminated in the text revision of the Diagnostic and
23
Statistical Manual of Mental Disorders (4th ed) (DSM-IV).
AD itself is now listed as an Axis III condition (general med-
ical conditions). Additional classifications under Axis I
(clinical disorders and other conditions that may be the
focus of clinical attention) are used when manifestations
of AD (such as behavioral disturbances, psychosis, depres-
sion, or aggressive personality) are serious enough to
require psychiatric intervention.
16
Jeste and Finkel suggested the following criteria to
diagnose psychosis due to AD and to exclude psychotic
symptoms due to schizophrenia or other conditions. Psy-
chosis in AD is the onset of hallucinations and/or delusions
in a patient who has previously met all criteria for the diag-
nosis of AD; the psychotic symptoms are present for at least
1 month, even if intermittently, and are severe enough to
disrupt life for the patient and others; and the symptoms
are not attributable to delirium, other medical conditions,
drug effects, schizophrenia, or other primary psychiatric
disorders.
Lewy body dementia (LBD) (also called senile demen-
tia of the Lewy body type) is a variant form of AD, named
for the presence of round, laminated bodies in neuronal
cytoplasm. The characteristic clinical manifestations are
fluctuating cognition, visual hallucinations, Parkinson-
ian motor symptoms, and frequent falls; in addition, behav-
ioral disturbances tend to be more prominent in patients
24
with LBD than in other patients with AD.
Although LBD is usually diagnosed in patients pre-
senting with symptoms characteristic of AD or PD, stud-
ies of the apolipoprotein E epsilon 4 allele have suggested
that the condition is etiologically related to AD but not to
25 15
PD. The apoE gene is a recognized risk factor for AD
but is not predictive of the onset of psychotic symptoms in
26
patients with AD.
Parkinson’s Disease
A common condition predisposing elderly patients to psy-
chotic symptoms is PD. In various reports, 20% to 60% of
10,27-29
patients with PD exhibit psychotic symptoms, of
which the most common are visual hallucinations and
10
paranoid delusions. In the majority of cases, psychosis
in patients with PD is extrinsic, resulting from treatment
with antiparkinsonian drugs (in contrast to intrinsic psy-
chotic symptoms, which occasionally appear as a result of
the progressive loss of dopamine-producing cells and pro-
30
gressive deterioration in various parts of the brain). The
onset of hallucinations and delusions is a recognized side
effect of various types of antiparkinsonian drugs, includ-
ing levodopa, dopamine receptor agonists, the dopamine
releaser amantadine, and the monoamine oxidase inhibitor
selegiline. Overall, hallucinations have been reported more
frequently than delusions in patients receiving dopamin-
31
ergic medications.
Hallucinations secondary to the use of antiparkin-
sonian drugs may be vivid. In a study of nondemented
patients with PD, daytime episodes of REM sleep were seen
more often in patients with hallucinations than in those
without hallucinations, suggesting that hallucinations in
this population may in some cases be related to dream
32
imagery secondary to a narcolepsy-like sleep disturbance.
A first-time onset of psychotic symptoms during treat-
ment with antiparkinsonian drugs is assumed to be drug
related. That assessment would be confirmed if a decrease
in drug dosage leads to a diminution or resolution of psy-
chotic symptoms, although drug-induced symptoms may
persist after dosage reduction. In contrast, psychosis due
to AD or schizophrenia is diagnosed only when the symp-
toms cannot be attributed to drugs or other known causes.
Schizophrenia
Within the general population, the reported prevalence
of schizophrenia among people over age 65 is 1% or below,
in contrast to reported rates of 35% among elderly patients
 Classification and Pharmacotherapy for Psychosis / Mintzer, Targum 201

in psychiatric hospitals and 12% among nursing home Table 1. Clinical Features of Psychosis in the Elderly
13
patients.
Schizophrenia in elderly patients most often represents Alzheimer’s Disease Parkinson’s Disease Schizophrenia
the continuation of a chronic condition that arose in ado-
Basis of Noncognitive Side effect of Primary
lescence or young adulthood, and the aging of the popu- psychosis manifestation antiparkinsonian abnormality
lation would therefore have only a limited effect on overall of underlying drugs
33 pathology
prevalence. The age range of highest risk is 20 to 35. In
Prior Uncommon Uncommon Typical for
a sizable minority of cases, however, the onset of psychotic psychiatric early-onset
symptoms occurs later in life. In a survey of male and history schizophrenia
female patients with schizophrenia, onset after age 35 Hallucinations More often More often More often
34 visual visual auditory
was reported in 17% of women and 2% of men. A some- Delusions More frequent Less frequent Typically
what higher incidence in older patients was estimated than than complex,
from a literature review (mainly European), which found hallucinations; hallucinations bizarre
typically
that close to one quarter of all cases of schizophrenia occur paranoid,
in people aged 40 or older, with the incidence of new cases simple,
35 nonbizarre
declining in progressively older age groups.
Suicide risk Low Low High
The age of onset is typically 3 to 4 years older in Clinical May persist or May resolve or Chronic
33
women than in men. Moreover, the gender ratio reverses course go into persist after
with increasing age: an analysis of data from a large catch- remission antiparkinsonian
drug dosage
ment area showed that the male-to-female ratio is 1.56:1 reduction
at ages 16 to 25, 1:1 at age 30, and 0.38:1 at ages 66 to 75.36
These gender-related differences may explain why a large
number of late-onset cases occur in menopausal women and
suggest that estrogenic activity may have some protective symptom or any 2 of the following: delusions, hallucina-
effect.37-39 tions, disorganized speech, grossly disorganized behavior,
DSM-III recognized schizophrenia occurring in patients or negative symptoms) for at least 1 month, causing sig-
over age 45 as a distinct condition, but DSM-IV does not. nificant social and occupational dysfunction. At least some
There are no significant differences in risk factors for evidence of the condition must have been present for at least
40
early-onset compared to late-onset schizophrenia, and 6 months (including the month of active-phase symptoms),
imaging studies of the brain have revealed no consistent and the symptoms must not be attributable to schizoaf-
differences in white matter hyperintensity volume based fective disorder, mood disorder, developmental disorder,
41
on age of onset. Nevertheless, there is continuing debate drug effects, or any general medical condition.
over the question of whether early-onset and late-onset
schizophrenia should be considered distinct conditions. Clinical Distinctions
Complicating this uncertainty is the frequent confu- The clinical features of psychosis often differ according to
sion between late-onset schizophrenia and the condition the diagnosis in which the symptoms occur. Table 1 com-
called paraphrenia or late paraphrenia. These terms, pares the presentations that characterize psychosis in
which do not appear in DSM-IV, are sometimes used inter- elderly patients with AD, PD, or early-onset or late-onset
changeably with late-onset schizophrenia. Late paraphre- schizophrenia.
nia is a British term for all delusional disorders occurring Relatively few patients with AD have personal or fam-
19-21
after age 60, which are often associated with a discernible ily histories of psychosis. Similarly, there may be no psy-
organic substrate, whereas late-onset schizophrenia is chiatric histories in patients with late-onset schizophrenia.
42
not. In contrast, elderly patients with early-onset schizophre-
Certain severe schizophrenic symptoms (such as audi- nia typically have extensive histories of psychiatric prob-
16
tory hallucinations with multiple voices arguing or delu- lems.
sions involving the belief that thoughts or actions have been With psychosis in PD, hallucinations are reported
31
forced on an individual by outside agencies) are called more frequently than delusions, whereas delusions are
Schneider first-rank symptoms. In general, symptoms are more common than hallucinations in patients with AD-
18
classified as positive (hallucinations, delusions, disorgan- related psychosis. With psychosis in AD, delusions are usu-
ized thought and behavior) or negative (poverty of speech, ally simple and nonbizarre, typically paranoid rather than
23
flat affect, anhedonia, apathy, social withdrawal). Beyond jealous, and hallucinations are more often visual than
the difficulties associated with psychotic symptoms, cog- auditory. With psychosis in schizophrenia, delusions tend
nitive dysfunction may independently impede reintegra- to be complex and bizarre, and hallucinations are more
43 16
tion to normal activities and functions. often auditory than visual.
The diagnosis of schizophrenia is based on the pres- A critical distinction between psychosis in patients with
ence of active-phase symptoms (a Schneider first-rank AD compared to schizophrenia is that suicidal ideation is
202 Journal of Geriatric Psychiatry and Neurology / Vol. 16, No. 4, December 2003
rare in patients with AD, whereas 50% of patients with
16
schizophrenia attempt suicide and 10% succeed.
Within the category of schizophrenia, certain clinical
distinctions between early-onset and late-onset disease
have been consistently reported. Compared to early-onset
schizophrenia, late-onset schizophrenia is associated with
fewer negative symptoms and less severe disorganization
40,44-46
of thought and speech.
In patients with psychotic symptoms secondary to
therapy with antiparkinsonian drugs, dosage reduction may
bring about an improvement in symptoms, but symptoms
can persist after dosage adjustment or even the cessation
of therapy. In addition, this strategy may also lead to a wors-
ening of PD symptoms.
The duration of psychosis in AD is variable. In some
cases, reported psychotic manifestations in patients with
AD are present for a limited time; in other cases, the con-
47,48
dition may persist or recur for years. The uncertainty
may in part reflect the previously mentioned question
about whether patients’ false beliefs represent true psy-
chotic delusions or cognitive deficits. Another source of
uncertainty is that the reduced reporting of psychotic
symptoms in patients with worsening dementia may rep-
resent a loss of the ability to express and describe delu-
sions and hallucinations rather than an actual remission
in their occurrence.49
Schizophrenia is characteristically a chronic condition
that has rarely been reported to go into remission in old
50
age. To make the clinical picture still more complex,
many elderly patients with schizophrenia develop demen-
51
tia, although it may be different in type from the demen-
52,53
tia typically seen in AD.
TREATMENT SAFETY
CONCERNS IN THE ELDERLY
In planning any form of pharmacotherapy in elderly
patients, there are legitimate concerns about the potentially
heightened impact of adverse effects and the diminished
abilities of patients to report and describe symptoms to their
physicians. Compliance may be poor in elderly patients with
psychosis. In addition, there are specific concerns about the
safety of antipsychotic drugs in this population. However,
elderly patients are not necessarily frail patients, and
automatic dosage reductions based on age may sometimes
result in diminished effectiveness without improved safety.
Although effective dosages tend to be lower in elderly
patients than in younger patients, starting dosages and
titration schedules should be based on diagnosis-specific
efficacy data for the selected agent rather than on age itself.
Age-Related Pharmacokinetic Changes
Elderly patients show a variety of physiologic changes
13
that can alter the pharmacokinetic profile of any drug.
The absorption of orally administered agents may be
affected by increased gastric pH and the slowing of gas-
tric emptying and intestinal transit. The diminution of total
body water, circulating volume, and plasma proteins, as well
as increases in body fat, will affect the volume of distri-
bution of a drug, depending on its protein binding and aque-
ous and lipid solubility characteristics. Age-related
decreases in hepatic and renal function will impair drug
metabolism, clearance, and excretion.
Comorbid Chronic Illness and Polypharmacy
In elderly patients with psychosis, clinical management
may be complicated by the presence of concomitant age-
related disorders, such as cardiovascular disease, malig-
nancy, and diabetes. Comorbid conditions can alter clinical
and laboratory profiles. In addition, patients with multi-
ple diagnoses may be in poor general health and therefore
more susceptible to drug toxicity. Finally, polypharmacy for
different disorders increases the risk for adverse reac-
tions and unpredictable drug interactions.
Adverse Effects of Antipsychotic Drugs
Antipsychotic treatment in the elderly incurs certain spe-
cific risks, beginning with drug-induced extrapyramidal
symptoms (EPS), including tardive dyskinesia (TD). The
risk for TD increases with age, cumulative dose, and the
54
duration of treatment. TD can occur and persist even at
55
low doses of conventional antipsychotic drugs. Conven-
tional antipsychotic agents can also produce marked anti-
cholinergic side effects, such as dry mouth, urinary
56
retention, and anxiety.
These drug-related adverse effects are of particular con-
cern in elderly patients with PD. As discussed in more detail
below, the risk for EPS is substantially lower with atypi-
cal neuroleptic agents than with older, traditional
54,57,58
agents, and switching from traditional to atypical
57
agents may allow the resolution of TD. Although dosage
requirements tend to be higher in patients with schizo-
phrenia than in those with AD-related psychosis, the eti-
ology of psychosis is not thought to be an independent
predictor of risk. Antipsychotic treatment can also cause
58
sedation and orthostatic hypotension and may impair
59
cognition in the elderly. The risk for side effects can be
minimized by slow upward titration from low starting
60
doses.
PHARMACOTHERAPY FOR
PSYCHOSIS IN THE ELDERLY
Conventional antipsychotic agents work by blocking
dopamine-2 receptors in the brain. As a result, they are
effective in treating the positive symptoms of schizophre-
nia but may be less effective in treating negative symp-
55,61
toms. They are also associated with serious adverse
 Classification and Pharmacotherapy for Psychosis / Mintzer, Targum
effects, including EPS. In addition, they may cause anti-
cholinergic effects, such as dry mouth and urinary reten-
56
tion, which are of particular concern in the elderly.
By comparison, the atypical antipsychotics offer
9 75
improved safety and effectiveness. These agents can con-
trol negative as well as positive symptoms, possibly because
they act at serotonin receptors as well as dopamine recep-
tors. In addition, the risk for EPS is lower with these
agents than with conventional antipsychotics.
Clinical Approaches
In patients with psychosis secondary to antiparkinsonian
drug treatment, low-dose antipsychotic therapy is often
required, using atypical agents with minimal risk for EPS.
Although the overall quality of treatment is better with
atypical antipsychotics, many physicians continue to use
traditional agents as first-line therapy in this population,
62
despite the risk for exacerbating EPS.
The treatment of psychosis in patients with AD typi-
cally begins with a limited course of low-dose antipsy-
chotic medication. Serotonergic antidepressants have also
63,64
proved useful for this condition, as have cholinesterase
65-67
inhibitors, especially in patients with LBD.68
Compared to the treatment of psychosis in AD, the
treatment of schizophrenia is expected to require ongoing
55
treatment at higher doses. Compared to patients with
early-onset schizophrenia, patients with late-onset schiz-
ophrenia may be more responsive to antipsychotic treat-
45,69
ment, but they also tend to be more aware of
70
drug-induced TD. Therefore, the use of an atypical
antipsychotic with minimal risk for EPS is especially
important.
Evaluations of Atypical Antipsychotics
The literature on the atypical antipsychotics is limited in
comparison to the literature on the traditional agents. It
is generally accepted that the most effective of the atypi-
cal antipsychotics is clozapine, and this agent’s anti-
cholinergic activity may be useful in controlling tremor
when used to treat drug-induced psychosis in patients
71
with PD. However, because it may cause agranulocyto-
sis, especially in elderly patients, frequent blood testing is
required to monitor the neutrophil and total leukocyte
counts. Consequently, clozapine is generally recommended
as second-line therapy for patients who have failed on
60
other antipsychotics.
Risperidone can reduce aggressive behavior and psy-
58
chosis in elderly patients. In nursing home patients with
AD, risperidone at 1 or 2 mg/d reduced psychosis and
aggression in about half of the patients; however, there was
72
an increased incidence of EPS at the higher dose. In
another study of patients with AD, risperidone and
haloperidol were both equivalent to a placebo in terms of
their effects on psychosis, but risperidone produced a
greater reduction in aggression than either haloperidol or
73
the placebo. In contrast, a recent meta-analysis of trials
203
in schizophrenic patients representing a wide age range
showed that risperidone at 6 to 16 mg/d was significantly
more effective than haloperidol in treating positive and neg-
74
ative symptoms. The use of risperidone has not been
associated with weight gain in the elderly.
In patients with AD and neuropsychiatric symptoms,
olanzapine at 5 or 10 mg/d was significantly more effec-
76
tive than a placebo and did not cause weight gain,
although studies of younger populations have reported
77,78
weight gain and disturbances in glucose metabolism.79
The possibility of an increased risk for falls in the elderly
60
has also been suggested, but controlled clinical trials in
76
this population have not confirmed such a risk. In patients
with psychosis secondary to antiparkinsonian drug ther-
apy, olanzapine at a mean peak dosage of 11.4 mg/d was
reported to be ineffective in reducing hallucinations and
tended to aggravate parkinsonian symptoms; its routine
80
use in this population has therefore been discouraged.
In a review of trials in schizophrenic patients of
varied ages, quetiapine produced long-term improve-
ments in positive and negative symptoms, with a placebo-
81
equivalent risk for EPS and minimal weight gain. The
low risk for EPS is advantageous in patients with PD-
82
related psychosis. In a subanalysis of an open-label trial
in patients with psychosis secondary to antiparkinsonian
drug treatment, quetiapine at 25 to 300 mg/d (median
peak 100 mg/d) was more effective in controlling visual hal-
28
lucinations than paranoid delusions. Evidence from
small, open-label trials suggests that quetiapine does not
worsen parkinsonian symptoms and is generally well tol-
28,83
erated. In a recent study, quetiapine at 25 to 300 mg/d
(median peak 100 mg/d) was well tolerated in nursing
84
home patients with AD.
Ziprasidone, the newest of the available atypical
antipsychotics, is effective against positive and negative
85
symptoms as well as depression, with somnolence and
85,86
nausea being the main side effects. It offers the high-
est degree of activity at serotonin receptors among agents
87
of this class. Ziprasidone is associated with low risks for
88,89
weight gain and EPS. However, concerns about QTc
90
interval prolongation have been raised. Although there
have been no reports of this effect leading to torsades de
pointes and sudden death, ziprasidone should not be con-
sidered a first-line agent for patients with comorbid car-
91
diovascular disease. To date, there have been no published
reports on the use of ziprasidone in the elderly.
CONCLUSIONS
Acute psychotic symptoms in the elderly population fre-
quently arise in association with AD, PD, and schizo-
phrenia. The clinical presentation of psychosis may be
different in these conditions, and the clinical diagnosis
should be considered when planning pharmacotherapy. In
comparison to the traditional antipsychotics, the atypical
antipsychotics offer an improved benefit-to-risk ratio, with
204 Journal of Geriatric Psychiatry and Neurology / Vol. 16, No. 4, December 2003
a markedly reduced risk for the development of EPS. Addi-
tional clinical research is needed to develop optimal treat-
ment guidelines and improved ways to measure the impact
of therapy on psychotic symptoms and on the overall qual-
ity of life for patients and their families.
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