As the population ages, the number of older patients with psychosis will greatly rise. This review
focuses on the etiology, biologic and clinical findings, and treatments of common causes of
psychosis in the elderly.
Psychosis is a common psychiatric symptom characterized by hallucinations and delusions. In the
elderly, causes may include schizophrenia and schizoaffective disorder, affective illnesses,
dementia, delirium, delusional disorders, substance-induced disorders, and Parkinson's disease.
Prevalence estimates of psychotic disorders in the elderly range widely from 0.2% to 4.75% in
community-based samples, and are as high as 10-63% in nursing home populations.[1,2] The
elderly currently account for about 12% of the US population, but that figure is expected to rise to
20% by the year 2030. As the population ages, the number of elderly patients with psychosis
will also increase significantly. Thus, it is an area of increasing interest and research. Biological
substrates underlie many psychotic symptoms and may be helpful in directing future research
into accurate diagnosis and treatment. The author will review some of the common faces of
psychosis in the elderly with respect to etiology and biologic findings, clinical correlates, and
Recent studies on psychosis related to Alzheimer's disease indicate that antipsychotic drugs have
equivocal efficacy in improving psychotic symptoms and may have side effects or risks that
outweigh their benefits. Behavioral interventions for agitation in dementia are showing some
promise. In older adults with schizophrenia, intramuscular ziprasidone was found to be effective,
and evidence is emerging for the use of hormone replacement therapy. For depression with
psychosis, a recent study found that the combination of an antidepressant with an antipsychotic is
no more effective than an antidepressant alone.
There is support for the use of antipsychotic drugs for all types of psychosis in the elderly. While
the atypical antipsychotics have a 'black box warning' on risk of death in elderly patients with
dementia, the typical antipsychotics carry an even higher risk of death and adverse effects.
Weighing the potential risks and benefits of treatment options is essential. Please refer to your
country's regulations regarding the use of antipsychotic drugs.
Psychosocial Correlates of Psychosis in the Elderly
Few studies have explored the prevalence of delusions in the nonclinical, elderly population or the
association between personality structure and delusions. Laroi and colleagues examined the
relationship between age and the prevalence of delusions and the association between personality
and delusion proneness. Nonclinical participants completed measures on delusions, hallucinations,
and personality traits. Elderly participants scored significantly higher than young participants on
the religious ideation factor, and correlational analyses revealed a significant relationship between
delusions and the openness facet of the personality measure. Overall, the study revealed that
delusional ideation is a relatively common experience for both young and elderly nonclinical
participants. In addition, findings were consistent with previous studies suggesting that
neuroticism and aspects related to neuroticism increase the risk for the development of psychotic
symptoms such as delusions.
Biopsychosocial risk factors associated with clinical late-onset psychosis include female sex, low
socio-economic status, the experience of immigration, and the presence of sensory or perceptual
deficits. Recent research by Giblin and colleagues compared the nature and extent of
adverse early life experiences, presence of maladaptive cognitive schemas, and morale in relation
to aging between older people with a diagnosis of late-onset psychosis, late-onset depression, or
healthy older volunteers (control group). They found that both the late-onset psychosis and late-
onset depression groups reported significantly higher levels of adverse life events than the control
group. The late-onset psychosis group also scored significantly higher on four out of five schema
domains (including rejection and disconnection, impaired autonomy and performance, other-
directedness, and over-vigilance and inhibition). Finally, the late-onset psychosis group had
significantly lower overall morale with regards to aging than the control group, likely reflecting
higher levels of loneliness and dissatisfaction.
Types of psychosis in the elderly
In a study of 140 geriatric outpatients that prospectively investigated psychosis in the elderly and
the associated clinical diagnoses, 36.7% of patients were diagnosed with dementia. In addition,
dementia accounted for the highest number of psychotic diagnoses in this study. Therefore, a
clinician should be highly suspicious of dementia in an elderly patient presenting with psychosis.
Alzheimer's disease currently affects about 7% of the population aged 65 and over. As the
population ages, the prevalence of Alzheimer's disease is expected to more than triple by the year
2050 from 4 million to approximately 14 million. Psychosis is one of the most prominent
noncognitive symptoms of Alzheimer's disease with prevalence estimates ranging from 30% to
50% and is associated with greater cognitive impairment, especially frontal/temporal
dysfunction, and possibly a more rapid course. There is considerable neurobiologic and
genetic evidence supporting a subtype of Alzheimer's disease based on the presence of psychotic
symptoms and possibly even of subtypes within psychotic Alzheimer's disease. Sweet and
colleagues have shown a possible association between psychosis in dementia and homozygosity
for the DRD1, DRD2, and DRD3 dopamine receptor gene alleles. Histopathological studies have
revealed differences in neuronal pathology in psychosis associated with dementia.[14,15] Zubenko
and colleagues found significantly increased densities of senile plaques and neurofibrillary
tangles in the prosubiculum and middle frontal cortex, respectively, in patients with Alzheimer's
disease and psychosis. Studies have also revealed differential neurotransmitter concentrations in
Alzheimer's patients with psychosis.[16,17] Finally, radiological studies have shown right and left
hemisphere differences in size,[18,19] and regional differences in blood flow and glucose
metabolism between psychotic and nonpsychotic patients with Alzheimer's disease.[20-22] Clinical
correlates associated with delusions in Alzheimer's disease include anosognosia (limited insight
into one's deficits), depression, global cognitive deficits, and elevated mood. Most patients with
hallucinations also had delusions, and paranoid delusions reportedly increased across the stages of
Jeste and Finkel have suggested the following operational criteria to aid clinicians in diagnosing
psychosis due to Alzheimer's disease and to exclude psychotic symptoms due to schizophrenia,
delirium, or other conditions. First, patients must meet all criteria for the diagnosis of Alzheimer's
type dementia. They must have the presence of visual or auditory hallucinations or delusions at
least intermittently for 1 month or longer, and the psychosis must not have been present
continuously prior to the onset of the symptoms of dementia. The psychotic symptoms must be
severe enough to cause some disruption in patients' or others' functioning and cannot be better
accounted for by another general medical condition, substance-induced psychosis, or occur
exclusively in the course of delirium. Finally, criteria for schizophrenia, schizoaffective disorder,
delusional disorder, or mood disorder with psychotic features must never have been met.
Treatment of psychosis and behavioral disturbances in Alzheimer's disease has largely focused on
the use of antipsychotics. Although atypical antipsychotics are more commonly used in the current
setting, typical antipsychotics are still used. Devanand and colleagues compared the efficacy
and side effects of two doses of haloperidol and placebo in the treatment of psychosis and
disruptive behaviors in patients with Alzheimer's disease. They demonstrated that standard-dose
(2-3 mg daily) haloperidol was effective and superior to low-dose (0.5-0.75 mg daily) haloperidol
for treating psychosis and disruptive behaviors in patients with Alzheimer's disease.
Extrapyramidal side effects were greater with the standard dose, but low-dose haloperidol did not
differ from placebo with regard to efficacy.
More recently, studies have focused on the use of atypical antipsychotics for treating psychosis
and agitation in Alzheimer's disease. In 2003, Schneider et al. evaluated the efficacy of
risperidone in reducing psychotic and aggressive symptoms in a subgroup of patients who fulfilled
operationalized criteria for psychosis in dementia. They found that the severity of both psychosis
and aggressiveness was reduced with risperidone compared with placebo in a robust and dose-
dependent way. In 2006, Tariot and colleagues evaluated the efficacy, safety, and tolerability
of quetiapine for treating psychosis. Two hundred and eighty-four participants were randomized
to receive quetiapine, haloperidol, or placebo. They found no differential benefit on any psychosis
measure between the groups, but did find that Brief Psychiatric Rating Scale (BPRS) scores
improved with quetiapine versus placebo and not quetiapine versus haloperidol. brief psychiatric
rating scale anergia scores, however, worsened with haloperidol versus quetiapine but not for
quetiapine versus placebo. Their overall conclusions were that participants treated with
quetiapine or haloperidol showed inconsistent evidence of improvement in agitation, and
tolerability was better with quetiapine versus haloperidol. Another group led by Ballard
evaluated the efficacy of quetiapine and rivastigmine compared with placebo for agitation in 31
people with dementia in institutional care, and they evaluated these treatments with respect to
change in cognitive performance. Compared with placebo, neither group showed significant
differences in improvement on the agitation inventory at 6 weeks or 26 weeks, and quetiapine was
associated with significantly greater cognitive decline. These results are echoed by the recent
Clinical Antipsychotic Trials of Intervention Effectiveness - Alzheimer's Disease (CATIE-AD)
which showed that there were no significant differences among treatments (olanzapine,
risperidone, quetiapine, or placebo) with regard to the time to discontinuation of treatment for
any reason. They found that the median time to discontinuation due to lack of efficacy favored
olanzapine and risperidone compared with quetiapine and placebo, but that the time to
discontinuation due to adverse events or intolerability favored placebo. The authors concluded
that the adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the
treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease.
Despite the equivocal efficacy and safety issues, which will be discussed later, the behavioral and
psychological symptoms of Alzheimer's disease (including psychosis) are most often managed with
antipsychotic drugs. A recent cross-sectional study in various geriatric care units (including
residential care facilities, nursing homes, group dwellings, rehabilitation units, etc.) was conducted
in Sweden to discover factors associated with the use of antipsychotic drugs. The investigators
found 11 independent factors that were significantly associated with the use of antipsychotics
including aggressive, verbally disruptive and wandering behaviors; hallucinatory and depressive
symptoms; male sex; living in a group dwelling for people with dementia; imposed mental
workload; the ability to rise from a chair; activities of daily living dependency; and lower age.
Alternative treatments for agitation and behavioral symptoms associated with dementia are
increasingly being considered. There is mounting evidence for the use of carbamazepine and
antidepressants such as trazodone and the selective serotonin reuptake inhibitors.[30-32]
Recently, Spira and Edelstein reviewed behavioral interventions for agitation in older adults
with dementia and found 23 articles describing interventions that targeted wandering, disruptive
vocalization, physical aggression, other agitated behaviors, and a combination of these behaviors.
They found that behavioral interventions showed considerable promise and concluded that studies
provided a good basis for future, more rigorously designed, intervention studies. Specific
interventions that seemed to be beneficial included stimulus control interventions for wandering,
differential reinforcement of other behaviors (DRO) for disruptive vocalization, and combinations
of antecedent control and DRO for reducing physical and verbal aggression and shower refusal,
stereotypy, and other behaviors.
The second most common cause of psychosis in the elderly, accounting for 20.4% of diagnoses in
psychotic geriatric patients, is depression. Although psychosis commonly accompanies bipolar
illness, these patients are much less frequently encountered in a geriatric psychiatry clinic.
Therefore, clinicians should seriously consider depression when evaluating elderly patients with
There is clinical evidence of late-onset depression (age > 65 years) being a distinct subtype of
depression. Specific findings indicate that patients with a late-onset first depressive episode are
more often women and are clinically characterized by more severe depressions and a higher
prevalence of psychosis than patients with early-onset depression. In fact, delusions are
present in up to 40% of older patients hospitalized for depression. Several studies have
revealed mixed findings on differences in biologic markers between delusional and nondelusional
depressed patients.[36-38] Simpson et al., however, found evidence of structural brain changes
in psychotic depression with more brainstem and frontal temporal atrophy and marked
enlargement of the third ventricles when compared with nonpsychotic depressed patients.
Treatment of psychotic depression generally may include pharmacotherapy or electroconvulsive
therapy. In a systematic review of pharmacologic treatment for unipolar psychotic depression,
Wijkstra and colleagues found no evidence that the combination of an antidepressant with an
antipsychotic is more effective than an antidepressant alone. The combination, however, was
statistically more effective than an antipsychotic alone. Thus, treatment of psychotic depression
should include an antidepressant and possibly the addition of an antipsychotic if the patient does
not respond. Some have argued that combined treatment of pharmacotherapy and psychotherapy
would be more effective, but research did not support this. In general, psychotic depression
does not respond well to pharmacotherapy, and this may be particularly true in older patients.
By contrast, electroconvulsive therapy outcomes are as favorable or perhaps even more
favorable in the presence of delusions.
The third most common cause of psychosis in the elderly, accounting for 12.2% of diagnoses in
psychotic geriatric patients, is delirium. The syndrome is characterized by a fluctuating
disturbance of consciousness, attention, and cognition. It may also be accompanied by
abnormalities in mood, perception, and behavior as well as sleep-wake cycle disturbances. The
pathophysiology of delirium is not well understood. Certain neuroanatomical and
neurotransmitter systems have been implicated, as well as particular brain regions. One study
using single photon emission computed tomography (SPECT) scans suggests that frontal or
parietal cerebral perfusion abnormalities occur in delirium.
Haloperidol remains the standard of treatment for delirium, but there is increasing evidence for
the use of atypical antipsychotics.[45,47] In an open label study, 24 delirious patients with a mean
age of 76.5 years were successfully treated with quetiapine doses ranging from 25 to 125 mg/day
(mean dose of 54.7 mg/day) and showed significant reductions in their delirium rating scale scores.
Schizophrenia in the elderly has been largely disregarded by researchers. Over 90% of published
papers on schizophrenia have excluded elderly persons with the disorder. Despite this,
approximately 23.5% of patients with schizophrenia developed the illness after the age of 40.
These persons are considered to have late-onset schizophrenia. Roughly 4% of persons with
schizophrenia have onset after the age of 60 and are considered to have very-late-onset
schizophrenia. Persons who develop schizophrenia before age 45, and who age with it, represent
about 85% of all persons with schizophrenia. Overall community prevalence estimates for
schizophrenia (both early and late onset) in individuals over the age of 65, however, ranges from
only 0.1% to 0.5%. Therefore, while schizophrenia represents a significant cause of psychosis
in the elderly, it is not as common a cause of psychosis in the elderly as dementia, depression, and
Later onset of schizophrenia seems to be more common in women.[52,53] In a survey of male and
female patients with schizophrenia, onset after age 35 was reported in 17% of women and 2% of
men. This is supported in part by the biologic findings in late-onset schizophrenia. There is
evidence of sex differences in brain volume loss and dopamine receptor numbers, possibly linked
to estrogen loss in women.[55,56] Other biologic findings associated with late-onset schizophrenia
include significant third ventricle enlargement. Elderly people with schizophrenia may also
have more dopamine receptors than age-matched normal controls but fewer than younger
patients. While some believe that the emergence of schizophrenia spectrum disorders in mid to
late life reflects a progressive neurodegenerative process, many studies support the view that late-
onset and very-late-onset schizophrenia are static encephalopathies.
The clinical presentations of late-onset schizophrenia and early-onset schizophrenia patients are
largely similar with some notable differences. Late-onset patients are more likely than their
earlier-onset counterparts to have visual, tactile, and olfactory hallucinations; abusive or
accusatory auditory hallucinations; a third-person running commentary; and persecutory
delusions. They are less likely to display a formal thought disorder or affective blunting.
For those patients with early-onset schizophrenia, there is a trend toward a reduction in positive
symptoms and debated changes in negative symptom.
As previously mentioned, schizophrenia is uncommonly found even in geriatric psychiatry clinics.
Only six out of 38 psychotic patients in one study had diagnoses such as mania, schizoaffective
disorder, schizophrenia, or delusional disorder. Therefore, clinicians should think of dementia,
depression, and delirium as causes of psychosis in their elderly patients ahead of schizophrenia.
Some clinical characteristics that distinguish schizophrenia from other forms of psychosis in the
elderly include having typically complex, bizarre delusions and auditory hallucinations.
Additionally, suicidal ideations are common in patients with schizophrenia and rare in other
Although the majority of research on treatment with antipsychotics has focused on younger
adults, there are a number of studies in older adults. Barak and colleagues recently conducted
a study in 21 elderly patients admitted to a psychogeriatric ward with acute psychosis related to
schizophrenia or schizoaffective disorder. Patients were treated for 3 days with flexible-dose
intramuscular ziprasidone injections for acute psychotic agitation. They found significant
reduction in the brief psychiatric rating scale after 3 days of treatment (P = 0.001) as well as a
significant decrease in the Behavioral Activity Rating Scale after each injection (P = 0.001).
Overall they had only one serious adverse event in a patient with benign prostatic hypertrophy
who developed urinary retention, and two side effects of mild severity that spontaneously resolved
(blurred vision and sedation). They concluded that intramuscular ziprasidone had acceptable
safety and efficacy in the management of acute psychotic agitation among elderly patients with
Ritchie et al. compared the efficacy and safety of olanzapine and risperidone in the treatment
of elderly patients with schizophrenia. As part of a three and a half year study, they initially
switched the treatment of 66 elderly patients with schizophrenia from typical antipsychotic
medications to either olanzapine or risperidone. Sixty-one patients from this study were
followed further for 6 months to see whether either treatment was superior in terms of efficacy or
safety. They found that both drugs were well tolerated and their use was associated with fewer
symptoms of schizophrenia and fewer adverse events than were seen when the patients were
taking a typical antipsychotic at baseline. Olanzapine seemed to be superior with regards to
quality of life. In a similar study, Barak and colleagues examined whether elderly chronic
schizophrenic patients would clinically improve if switched to olanzapine from previous typical
neuroleptic treatment. The mean duration of treatment was 289 days and the mean dose of
olanzapine was 12.9 mg. They found no significant change in body weight and patients had
clinically meaningful change in positive and negative psychotic symptomatology.
One monumental study, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE),
examined the relative effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
The researchers found that olanzapine was the most effective in terms of the rates of
discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared
similar to that of quetiapine, risperidone, and ziprasidone. Unfortunately, this study did not
include individuals over the age of 65.
An interesting new possibility for treatment of schizophrenia in older women was raised by a
recent study examining the effect of HRT on cognitive function in women with chronic
schizophrenia. Ko and colleagues assessed the cognitive effects of adjuvant HRT when used to
treat premenopausal women with chronic schizophrenia using an 8-week, double-blind, placebo-
controlled randomized trial. They found significant improvements in the Scale for the Assessment
of Negative Symptoms and in cognitive functioning in the HRT group compared with the placebo
group. Although this research was done in premenopausal women, it raises the possibility of using
HRT for older, postmenopausal women, especially in light of the biologic findings related to loss of
estrogen in late-onset schizophrenia as previously discussed.
Special Treatment Considerations
Treatment of psychosis in the elderly requires special attention to age-related issues including
pharmacokinetic changes, comorbid illnesses and polypharmacy, and possible adverse effects of
antipsychotic drugs. One commonly known adverse effect of the typical antipsychotics is
extrapyramidal symptoms (or EPSs) which include Parkinsonism (bradykinesia, tremor,
cogwheeling rigidity, masked facies), dystonia (muscle spasms that may be painful), and akathisia
(feelings of inner tension and anxiety and a compulsive drive to move the body evidenced by
pacing and restlessness). The elderly may be especially sensitive to this and all side effects.
Although extrapyramidal symptoms are usually treated in adults with anticholinergic drugs such
as diphenhydramine or benztropine, these drugs may cause cognitive impairment, worsening of
constipation, and other problems in the elderly, so they must be used with caution. Of the atypical
neuroleptics, risperidone is associated with the most extrapyramidal symptoms and clozapine is
associated with the least. Clinical impression among many providers is that quetiapine and
olanzapine also have fairly low incidence of extrapyramidal symptoms.
Another serious adverse effect of antipsychotic drugs is tardive dyskinesia. Tardive dyskinesia is a
delayed onset movement disorder that continues even after the drug has been discontinued and is
characterized by repetitive, purposeless, involuntary movements. The overall mean prevalence of
tardive dyskinesia among chronically neuroleptic-treated patients is approximately 24%. The
annual incidence in younger adults is 4-5%. Aging, however, is a major risk factor for tardive
dyskinesia. Research by Jeste and Caligiuri suggests that the annual incidence in patients
older than 45 years is over 30%. Others have found that elderly persons treated with conventional
antipsychotics had four to five times the risk of developing tardive dyskinesia than the younger
patients. Other risk factors for the development of tardive dyskinesia include the use of
anticholinergic medications for those over 40 years of age, long duration of neuroleptic exposure
for those over 18 years of age, female sex, mood disorders, 'organic' brain dysfunction or damage,
diabetes mellitus, and early extrapyramidal side effects.[69,71] Several studies have found a lower
incidence of tardive dyskinesia associated with atypical versus typical antipsychotics.[72,73]
A third major adverse effect of antipsychotic drugs is weight gain. In 2003, the US Food and Drug
Administration (FDA) required all manufacturers of atypical antipsychotics to change their
labeling to include a warning about the risks of hyperglycemia and diabetes with atypical
antipsychotics. These findings are somewhat clouded by the fact that drug-naïve schizophrenics
also appear to have an increased incidence of impaired glucose metabolism. In 2006, Klein and
colleagues conducted a 16-week double-blind, placebo-controlled trial to evaluate the
effectiveness of metformin in managing weight gain in 39 patients (ages 10-17) whose weight had
increased by more than 10% in less than 1 year on an atypical antipsychotic. They demonstrated
that weight in patients receiving metformin stabilized with no serious adverse events, while those
receiving placebo continued to gain weight.
Finally, the most serious adverse event associated with the use of antipsychotic drugs is an
increased risk of death. In April 2005, the US Food and Drug Administration requested that all
manufacturers of atypical antipsychotic medications add a 'black box warning' to their
prescribing information regarding the use of these medications in elderly patients with dementia-
related psychosis because of an increased risk of death compared with placebo. According to the
US Food and Drug Administration, an analysis of 17 placebo-controlled trials (modal duration of
10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 and
1.7 times that seen in placebo-treated patients. The US Food and Drug Administration further
stated that, over the course of a typical 10-week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared with a rate of about 2.6% in the placebo group. Although the
causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart
failure, sudden death) or infectious (e.g. pneumonia) in nature. In 2005, Schneider and colleagues
 performed a metaanalysis of 15 randomized, double-blind, placebo-controlled, parallel group
trials of atypical antipsychotic use in elderly patients with dementia and found that death
occurred more often in patients receiving atypical antipsychotic therapy than in those receiving
placebo [118 (3.5%) versus 40 (2.3%), respectively]. This increased risk, however, was identified
only when all drugs were pooled for analysis; metaanalyses of individual drugs did not show a
statistically significant increased risk. Unfortunately, the US Food and Drug Administration
warning described above did not address the increased risk of death associated with typical
antipsychotic drug use in the elderly. Several studies have found that there is a significantly higher
risk of death associated with the use of typical antipsychotic drugs than with atypical
antipsychotic drugs in older patients.[77,78]
Psychosis in the elderly occurs most commonly in relation to dementia, depression, or delirium,
though schizophrenia and bipolar illness are also common causes. Conditions not discussed, but
which may lead to psychosis, include various medical conditions such as Parkinson's disease. The
clinical presentation of psychosis is often different in these conditions and appropriate diagnosis
should direct treatment. Generally speaking, there is ample evidence of using antipsychotic drugs
for all types of psychosis in the elderly. While the atypical antipsychotics now carry a 'black box
warning' on risk of death in elderly patients with dementia, the typical antipsychotics are
associated with an even higher risk of death, as well as other adverse effects. Weighing the
potential risks and benefits of treatment options is essential. Although antipsychotic drugs are
commonly used for different types of psychoses in the elderly, it should be noted that none of these
drugs (nor any other psychotropic drugs) has been approved by the US Food and Drug
Administration for use in any psychosis other than schizophrenia. Please refer to your country's
regulatory approvals regarding the use of these antipsychotic drugs.
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Am J Geriatr Psychiatry 2004; 12:437-439.
The author: Professor Yasser Metwally
Professor of neurology, Ain Shams university school of medicine,Cairo, Egypt
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