Curr Psychiatry Rep (2015) 17: 1

DOI 10.1007/s11920-014-0542-0

GERIATRIC DISORDERS (W MCDONALD, SECTION EDITOR)

Late-Life Psychosis: Diagnosis and Treatment

Michael M. Reinhardt & Carl I. Cohen

Published online: 24 January 2015

# Springer Science+Business Media New York 2015

Abstract Psychosis is one of the most common conditions in Introduction

later life with a lifetime risk of 23 %. Despite its high prevalence,
late-onset psychosis remains a diagnostic and treatment dilem- Ernst von Feuchtersleben has been credited with introducing
ma. There are no reliable pathognomonic signs to distinguish the term “psychosis” in 1845 by combining the Greek “psy-
primary or secondary psychosis. Primary psychosis is a diagno- che” (life, soul, mind) and “osis” (an abnormal condition
sis of exclusion and the clinician must rule out secondary causes. thereof), although Karl Friedrich Canstatt apparently used
Approximately 60 % of older patients with newly incident the term as early as 1841 [1]. In modern medical parlance,
psychosis have a secondary psychosis. In this article, we review “psychosis,” according to the International Classification of
current, evidence-based diagnostic and treatment approaches for Diseases, tenth revision (ICD-10), “simply indicates the pres-
this heterogeneous condition, emphasizing a thorough evalua- ence of hallucinations, delusions, or a limited number of
tion for the “six d’s” of late-life psychosis (delirium, disease, several abnormalities of behavior, such as gross excitement
drugs dementia, depression, delusions). Treatment is geared and overactivity, marked psychomotor retardation and cata-
towards the specific cause of psychosis and tailored based on tonic behavior” [2]. The Diagnostic and Statistical Manual of
comorbid conditions. Frequently, environmental and psychoso- Mental Disorders, Fifth Edition (DSM-5) aligns with the ICD-
cial interventions are first-line treatments with the judicious use 10, stating that psychotic disorders are defined by “abnormali-
of pharmacotherapy as needed. There is an enormous gap ties in one or more of the following five domains: delusions,
between the prevalence of psychotic disorders in older adults hallucinations, disorganized thinking (speech), grossly disorga-
and the availability of evidence-based treatment. The dramatic nized or abnormal motor behavior (including catatonia), and
growth in the elderly population over the first half of this century negative symptoms.” [3••]. However, in the appendix,
creates a compelling need to address this gap. the DSM-5 defines “psychotic features” as characterized by
delusions, hallucinations, or formal thought disorder.
Late-life psychosis is strikingly prevalent in older adults,
Keywords Late-life psychosis . Geriatric psychosis . presenting in 5–15 % of elderly geropsychiatric inpatients, 10
Psychosis . Geriatric . Elderly . Dementia . Neurocognitive to 62 % of nursing home patients, and as high as 27 % of
disorders . Schizophrenia . Delirium . Primary psychotic community-dwelling psychiatric outpatients [4, 5]. The life-
disorders . Secondary psychotic disorders . Psychotic disorder time risk for psychotic symptoms in the elderly is up to 23 %,
due to another medical condition . Delusional disorder . with dementia being the main contributing factor [4, 5]. De-
Schizoaffective disorder . Major depressive disorder . Bipolar spite its widespread prevalence in older adults, late-onset
disorder . Substance/medication-induced psychotic disorder psychosis frequently remains a diagnostic and treatment
dilemma.
This article is part of the Topical Collection on Geriatric Disorders
M. M. Reinhardt (*) : C. I. Cohen
Department of Psychiatry and Behavioral Sciences, Division of
Diagnosis and Treatment of Secondary Late-Life
Geriatric Psychiatry, SUNY Downstate Medical Center, 450
Clarkson Ave, Box 1203, Brooklyn, NY 11203, USA Psychoses
e-mail: [email protected]
C. I. Cohen Psychoses can be either primary (caused by a psychiatric
e-mail: [email protected] disorder) or secondary (due to a medical or neurological
1 Page 2 of 13 Curr Psychiatry Rep (2015) 17: 1

disorder). About three fifths of psychotic disorders in later life 3. An absence of past psychiatric history
are due to a secondary condition [4, 5]. The estimated preva- 4. Limited response to psychiatric treatment
lences of the conditions most commonly associated with late- 5. Symptoms more severe than might be expected
life psychosis are listed in Table 1. 6. Psychopathology developed following an abrupt person-
ality change
7. Comorbid medical condition(s) with a known association
History and Physical Examination with mental illness (psychosis)
8. Abnormalities of cognition, particularly memory and
Accurate diagnosis of psychosis in the elderly is of critical consciousness
importance, particularly given the presence of serious medical
conditions that may masquerade as psychotic illness [6••, 7]. There is no consensus approach for the initial diagnostic
Because there are no pathognomonic signs to easily distin- testing of psychotic illness in young or old adults [6••, 10].
guish primary from secondary psychotic disorders, a primary Most clinicians conduct a complete blood count (CBC) and
psychotic disorder is the final consideration following the comprehensive metabolic panel (CMP) but also add thyroid-
elimination of secondary causes of psychosis [3••]. A careful stimulating hormone (TSH), vitamin B12, folate, rapid plasma
history and physical examination are the sine qua non of the regain (RPR), and erythrocyte sedimentation rate (ESR). Au-
workup of a psychotic disorder. Moreover, no diagnostic toimmune antibody screens, HIV testing, and toxicology may
evaluation of late-life psychosis should be considered com- be done when indicated. Often, a head MRI or CT scan is
plete without collateral history. done; EEG and polysomnography are done if indicated by
A variety of risk factors associated with aging make older history.
adults more prone to psychosis [8•]: A useful way to think about the diagnosis of psychotic
disorders is to use the “six d’s” approach, that distinguishes
& Sensory deficits disorders based on the timeline of their presentation (see
& Social isolation Table 1). In the sections that follow, we address each of the
& Cognitive decline “d’s”.
& Medical comorbidities
& Polypharmacy
& Age-related changes in pharmacokinetics and Delirium
pharmacodynamics
& Comorbid psychiatric illnesses such as dementia and Except for some minor rewording, the diagnosis of delirium in
delirium the DSM-5 has not changed from the DSM-IV-TR. It is a
& Age-related changes in cerebral structures such as condition which often goes unrecognized and contributes to
frontotemporal cortices excess morbidity and mortality. A recent review by Inoue et al.
& Neurochemical changes associated with aging noted a prevalence rate as high as 50 % among the hospital-
ized elderly in the intensive care unit [11••]. This same review
Clinical presentations that should raise suspicion of sec- and another recent meta-analysis by Witlox and coauthors
ondary causes of psychosis include [9] the following: [12] found that delirium had an appreciable impact on the
relative risks of mortality, diagnosis of dementia, institution-
1. Unusual age of onset of the presenting psychiatric alization, functional decline, and falls.
symptoms Perceptual disturbances are common during a delirium,
2. An absence of family history of mental illness with 40 to 70 % of elderly patients experiencing hallucinations

Table 1 “Six d’s” of psychotic disorders [3••, 4, 123]

Course Proportion of all causes of psychoses Type of psychoses

Delirium Days to weeks 10 % Secondary

Drugs, alcohol, toxins Days to months 11 % Secondary
Disease Days to months 10 % Secondary
Depression and other affective disorders Weeks to months 33 % (depression) Primary
5 % (bipolar)
Dementia Months to years 40 % Primary
Delusional disorder and schizophrenia-spectrum disorders Months to decades Delusions (2 %) Primary
Schizophrenia (1 %)
Curr Psychiatry Rep (2015) 17: 1 Page 3 of 13 1

and 25 to 79 % experiencing delusions, depending on the dementia. History and physical and neurological evaluations
subtype of delirium and the population being sampled [13••, remain crucial to accurate diagnosis and treatment. While
14, 15]. Psychosis is more common with patients experiencing physical and neurological examinations are non-specific for
the hyperactive variant of delirium; however, a recent study of primary psychoses, they may point to a secondary etiology of
oncology patients found prominent perceptual disturbances psychosis or conditions that may be exacerbating the primary
(50 %) and delusions (43 %) in hypoactive delirium [13••]. disorder [26]. Table 2 lists potential medical etiologies of late-
Factors that predispose to delirium include dementia, cog- life psychoses. The acronym “MINE,” outlined in Table 2, is a
nitive impairment, a previous history of delirium, a history of useful mnemonic for recalling the principal medical etiolo-
functional impairment, visual impairment, hearing impair- gies. For an exhaustive reference on the diagnosis and poten-
ment, comorbidities/severity of illness, depression, history of tial causes of psychosis across the lifespan, we recommend the
TIA/CVA, alcohol use disorders, and age >75 years [11••]. excellent book by Cardinal and Bullmore, The Diagnosis of
Importantly, a delirium episode is often the first sign of de- Psychosis [27•].
mentia. Rahkonen and colleagues [16] observed that dementia
was diagnosed immediately after delirium symptoms had Table 2 Common medical causes of psychosis in older persons [8••, 19,
subsided in 27 % of patients and was present in 55 % of 27•, 123, 124]
individuals on 2-year follow up. Metabolic • Vitamin B12 deficiency
The prompt diagnosis of the underlying etiology of • Folate deficiency
delirium is essential. Validated screening tools for delirium • Electrolyte abnormalities
such as the Confusion Assessment Method (CAM) and ○Sodium
○Potassium
CAM-Severity (CAM-S) can be used [17, 18••]. EEG and ○Calcium
neuroimaging need not be done routinely but should be ○Magnesium
ordered as indicated by the clinical features of a particular • Acute intermittent porphyria
case. EEG has a typical pattern in delirium of diffuse • Hepatic encephalopathy
• Uremic encephalopathy
slowing with increased theta and delta activity and poor • Other nutritional deficiencies
organization of background activity, but this provides little • Anoxia/hypoxia
insight into the underlying etiology [19]. Ordering an EEG • Hypercarbia
may be most useful in difficult-to-evaluate cases, evaluat- Infections • Meningitides
ing sudden deterioration in patients with dementia, and • Encephalitides (e.g., herpes, etc.)
• Neurosyphilis
evaluating for non-convulsive status epilepticus or atypical • HIV/AIDS
partial complex seizures [11••]. • Pneumonia
Environmental and behavioral treatment strategies are best Neurological • Parkinson’s disease
employed initially, with antipsychotic medications reserved • Epilepsy
only for severe agitation rather than as a standing medication ○Temporal lobe epilepsy
○Grand mal
[10]. If necessary, the best evidence suggests the use of oral or
○Non-convulsive status epilepticus
IM haloperidol or olanzapine for optimal patient outcomes • Subdural hematoma
and cost-effectiveness [20]. However, there is no FDA- • Cerebrovascular events
approved pharmacologic treatment of delirium. Prevention • Huntington’s disease
• Multiple sclerosis
and treatment strategies are covered extensively by guidelines
• Amyotrophic lateral sclerosis
(e.g., NICE, APA, and others) and recent review articles [11••, • Tumors
21–24, 25•]. ○Temporal lobe—auditory hallucinations
○Occipital lobe—visual hallucinations
○Limbic—delusions
Disease
○Hypothalamus—delusions
• Limbic encephalitides
In DSM-5, all conditions attributable to other medical causes • Autoimmunereference
have been renamed from “[Condition] due to a general med- ○Paraneoplastic syndromes
○Systemic lupus erythematosis
ical condition” to “[condition] due to another medical condi-
○Vasculitides
tion.” [3••]. The DSM-5 diagnosis of a psychotic disorder due • Sleep disorders (narcolepsy)
to another medical condition requires the presence of delu- • Other genetic/heritable conditions
sions or hallucinations that are attributable through history, ○Likely to have been diagnosed in childhood
physical examination, or testing to another medical condition Endocrine • Hypo-/hyperthyroidism
• Adrenal disease
[3••]. The diagnosis is further specified according to the
• Hypo-/hypoglycemia
etiology and whether it is “with delusions” or “with halluci- • Hypo-/hyperparathyroidism
nations.” The prevalence is exclusive of delirium and
1 Page 4 of 13 Curr Psychiatry Rep (2015) 17: 1

The treatment of these conditions should be based on & Sedatives, hypnotics, or anxiolytics
addressing the underlying medical condition. Behavioral and & Stimulants (inclusive of amphetamine-type substances,
environmental strategies should be first-line treatments for cocaine, or other unspecified stimulants)
these psychoses; however, short-term treatment with antipsy- & Other/unknown substances
chotic medications may be indicated due to symptom severity.
This treatment should be time limited and dose limited and During withdrawal, the following substances/classes of
medication choice tailored to the needs of the specific patient. substance have been implicated [3••]:
According to general expert guidance on medication
choice in the elderly, for patients with major metabolic & Alcohol
conditions (diabetes, dyslipidemia, obesity), it is best to avoid & Sedatives, hypnotics, or anxiolytics
clozapine, olanzapine, and conventional antipsychotic medi- & Other/unknown substances
cations [28]. In the case of congestive heart failure or
prolonged QTc, clozapine, ziprasidone, and conventional an- In theory, any medication that crosses the blood-brain
tipsychotics should be avoided [28]. Risperidone (first line) barrier could induce psychotic symptoms; however, certain
and quetiapine (second line) are the medications of choice in medications and classes of medications have been more com-
cases with comorbid obesity, cognitive impairment, diabetes, monly associated with psychosis [8••]:
diabetic neuropathy, xerostomia, xerophthalmia, or
dyslipidemia [28]. & Antiparkinson drugs
& Anticholinergic drugs
Drugs, Alcohol, and Toxins & Cimetidine
& Digoxin
The problematic use of substances (illicit or prescribed) re- & Antiarrhythmic drugs
mains an under-recognized problem in the elderly [29]. While & Corticosteroids
drug and alcohol use might continue to be less prevalent than & Interferon
in other age groups, the overall prevalence in the elderly is
rising [30••, 31]. Recent predictive modeling estimates that There are no controlled studies on the treatment of
the prevalence of substance use disorders in adults 50 and over substance/medication-induced psychotic disorders in the el-
(across genders, race groups, and age groups) will double derly. Whenever possible, the safe withdrawal (or dosage
from 2.8 million (average) in 2002–2006 to 5.7 million by decrease) of the offending substance/medication should be
2020 [31]. This is attributable to the aging of the baby initiated as first-line treatment. Psychosocial interventions
boomers who have a higher lifetime rate of alcohol and drug should be encouraged such as motivational enhancement ther-
use than previous generational cohorts [31]. apy, CBT, and support groups for substance cessation al-
According to DSM-5, psychosis resulting from substance though many of these approaches are not validated in the
use is termed a substance/medication-induced psychotic dis- elderly population [33••]. Of the pharmacologic approaches
order [3••]. Multiple substances have been associated with for substance cessation, naltrexone has the most evidence
psychosis according to DSM-5. The diagnosis of a supporting its use in the elderly [33••].
substance/medication-induced psychotic disorder is
established by the presence of delusions and/or hallucinations
and is attributable to substance intoxication or withdrawal Dementia (Now: Neurocognitive Disorders)
through a plausible substance/medication mechanism [3••].
Screening for problematic drug and alcohol use is vital to Psychosis is found most commonly among persons with
accurate diagnosis in this population. The CAGE consists of neurocognitive disorders. In the instances in which patients
only four questions but is a useful and validated tool for present with cognitive changes and psychotic illness, revers-
detecting alcohol misuse in elderly populations [32]. Urine ible causes of cognitive decline and associated psychosis must
toxicology should be conducted to evaluate for drug usage. be addressed initially. Moreover, during the evaluation of a
During intoxication, the following substances and sub- neurocognitive disorder with psychotic symptoms, careful
stance classes are considered psychotogenic [3••]: attention must also be paid to the presence of sensory deficits,
particularly visual impairment, that may contribute to the
& Alcohol presence of psychotic symptoms [34•].
& Cannabis There have been extensive changes in the DSM-5 nomen-
& Phencyclidine clature [3••]. Previously called “dementias,” the
& Other hallucinogens neurocognitive disorders are classified according to
& Inhalants neurocognitive domains and the characteristic deficits of these
Curr Psychiatry Rep (2015) 17: 1 Page 5 of 13 1

domains within specific disorders. Deficits must be present in phenomenological differences. The Cache County study
at least one of the following neurocognitive domains: found the prevalence of hallucinations to be similar between
Alzheimer’s disease and vascular dementia, while delusions
& Complex attention were found to be more prevalent in Alzheimer’s disease
& Executive function versus vascular dementia (23 vs 8 %) [43].
& Learning and memory Neurocognitive disorder with Lewy bodies (NCDLB) also
& Language known as dementia with Lewy bodies has three main classes of
& Perceptual motor neuropsychiatric symptoms: visual hallucinations, misidentifi-
& Social cognition cation syndromes, and delusions [44]. Most common are visual
hallucinations with prevalence rates of 25 to 83 %, while delu-
The diagnosis has been subdivided into “major” and “mild” sions have reported rates between 13 and 75 % of patients [45].
forms. The diagnostic criteria of a major neurocognitive disor- Recent studies have reported 29 to 50 % rate of misidentifica-
der are based on a significant decline of cognitive function tion syndromes such as Capgras syndrome or phantom boarder
from the previous level of performance in one or more of the syndrome in NCDLB [45–47]. The rate of misidentification
cognitive domains whereas mild neurocognitive disorder re- syndromes was found to have a 4 % point prevalence and
quires a less severe decline in at least one neurocognitive 22 % period prevalence for patients with Alzheimer’s disease,
domain with no appreciable decline of function. making this a useful clinical diagnostic indicator [47]. Approx-
The prevalence of psychotic symptoms in Alzheimer’s imately 43 % of patients with NCDLB have visual hallucina-
disease ranges from 16 to 70 % (median 37 %) for delusions tions in the earliest phases of the illness. Early visual hallucina-
and 4 to 76 % (median 23 %) for hallucinations [35, 36, 37•, tions with or without clinically meaningful cognitive decline
38]. The rates of psychoses vary by the stage of illness. It is should always raise the suspicion of Lewy body disease [45].
found most commonly in the middle stages of the illness, with Psychosis is also a common sequelae of Parkinson’s dis-
a 20 % rate in the early stages of Alzheimer’s disease and up to ease and neurocognitive disorder due to Parkinson’s disease.
50 % by the third or fourth years of illness (overall 30 to 50 %) While the hallucinations of Parkinson’s disease (approximate-
[35, 36, 37•, 38]. ly 25 %) have been described as benign hallucinosis and re-
Visual hallucinations are the most common type of hallu- markable for retained insight, the hallucinations of
cination in Alzheimer’s disease patients, followed by auditory neurocognitive disorder due to Parkinson’s disease (previous-
and, less commonly, other types (olfactory, tactile, gustatory) ly Parkinson’s disease with dementia or PDD), seen in about
[36]. This differs from primary psychoses where auditory hal- 60 % of these patients, have been described as more complex
lucinations are most common. The hallucinations experienced and distressing, and present with a general loss of insight [48].
most commonly involve people from the past (e.g., deceased Visual hallucinations are more common than delusions in
relatives), intruders, animals, and objects. The most frequent PDD patients [49]. As with the other neurocognitive disor-
types of delusions experienced during the course of ders, these symptoms worsen prognosis, intensify caregiver
Alzheimer’s disease are false beliefs of theft, infidelity of distress, and increase the likelihood for institutionalization
one’s spouse, beliefs of abandonment, believing that their [50]. It is important to underscore the need to rule out extrinsic
house is not their home, and persecution [36]. Delusions tend causes of hallucinations, i.e., antiparkinson’s medication/
to decreases in later stages. Some symptoms, although dopaminergic agents.
appearing to be delusions or hallucinations, may be misiden- Given the multitude of studies that have described issues
tifications due to cognitive deficits, e.g., mirror sign (mistakes with the safety profiles of medications used to treat psychosis
self in mirror for someone else) and TV/magazine sign (belief in the elderly, the consensus across the varied guidelines is a
that people on TV or in magazines are present and real) [36]. uniform recommendation for first-line non-pharmacological
There is increasing evidence supporting a subtype of approaches [51••, 52••]. Every effort should be made to insti-
Alzheimer’s disease based on the presence of psychotic symp- tute these treatments first, particularly in cases in which pa-
toms that has an association with dopamine receptor gene tients themselves are without subjective distress related to
alleles, an increased density of plaques and tangles in the their psychotic symptoms. Moreover, it is important to allevi-
prosubiculum and frontal cortex, APOe genotypes, and differ- ate “unmet needs” such as sensory deficits (e.g., hearing aids,
ences in neurotransmitter concentrations [39, 40••]. The glasses), social isolation of patients, environmental over- or
anterior cingulum has recently been implicated in the presence under-stimulation, and so forth [51••, 52••].
of certain neuropsychiatric symptoms, particularly irritability, Psychosocial strategies for dementia with the strongest
apathy, agitation, dysphoria, and nighttime behavioral evidence at present include alleviating caregiver burden (care-
disturbances [41•, 42•]. giver education, support systems), music therapy, cognitive
Psychosis associated with vascular dementia has been stimulation therapy, Snoezelin therapy (multisensory stimula-
found to be epidemiologically similar with some tion), behavioral management (by professionals), and staff
1 Page 6 of 13 Curr Psychiatry Rep (2015) 17: 1

training/education [51••, 52••]. Less convincing evidence ex- disturbances in neurocognitive disorders and are tolerated well
ists for strategies such as reality orientation, caregiver- when compared to antipsychotic medications and placebo
instituted behavioral management, validation therapy, remi- [68••]. Carbamazepine has show utility in small studies for
niscence therapy, therapeutic activity programs, and physical the treatment of agitation in neurocognitive disorders, but po-
environment stimulation strategies [51••, 52••]. tential adverse effects frequently outweigh benefits [69, 70].
When these first-line approaches have failed, and moderate Prazosin has one positive study for the treatment of agitation
or greater symptoms remain, pharmacologic approaches in neurocognitive disorders, but further research is needed
should be considered. This remains the consensus recommen- [71].
dation despite the associated risks of these approaches. The Targeted treatment for patients suffering from Parkinson’s
first step of a rational, evidence-based psychopharmacologic disease (PD) or NCDLB and secondary psychosis must be
approach to psychotic symptoms in dementia should include initiated cautiously due to a much-heightened risk of extrapy-
the appropriate use of acetylcholinesterase inhibitors ramidal symptoms in these patients. It is critical to adjust
(donepezil, rivastigmine, galantamine) and memantine. Be- antiparkinson’s medications before initiating antipsychotic
yond their modest benefits for cognition, these medications medications, starting with medications with the least effective-
have been shown to reduce behavioral symptoms (including ness, as many of these medications may induce psychosis [72,
psychosis) and possibly decrease the need for additional phar- 73••]. Typical antipsychotic medications should not be used in
macologic agents [53, 54, 55••]. these patient populations. Clozapine has the most consistent
When initial treatments fail, consideration should be given evidence for efficacy in the PD population although its use has
to the use of antipsychotic medications. Following the 2005 been limited by concerns about agranulocytosis, anticholiner-
publication of a large meta-analysis noting an increased (OR gic side effects, orthostatic hypotension, and the need for
1.7) risk of mortality in patients with dementia with psychosis blood monitoring [72, 74]. Quetiapine has inconsistent evi-
treated with atypical antipsychotic medications, the FDA is- dence for its benefit in this population but is still used prefer-
sued a black box warning regarding the use of antipsychotic entially over clozapine because of the aforementioned con-
medications in this population [56]. It should be noted that the cerns [72, 74]. Dosing ranges recommended for PD and
absolute increase in mortality is approximately 1 in 50 to 1 in NCDLB patients are [52••] the following:
100 patients. Principal causes of mortality are cardiovascular,
infectious, and cerebrovascular causes [56, 57]. There is con- & Clozapine 6.25 to 50 mg
troversy in the literature with some studies finding no increases & Quetiapine 12.5 to 150 mg
in mortality, that the mortality risk may be associated with
higher doses of medication, and that some medications may Donepezil and rivastigmine have shown some benefits for
be safer, e.g., quetiapine has the lowest associated mortality the treatment of psychosis in the PD population [72]. Recently,
rates [58, 59••]. Of note, data from the CATIE-AD trial have pimavanserin, a serotonin inverse agonist, successfully complet-
revealed an increased decline in cognition in those treated with ed phase 3 trials and has been shown to have a greater decrease
atypical antipsychotics versus those treated with placebo [60••]. in Scale for Assessment of Positive Symptoms in Parkinson’s
Perhaps due to a dearth of effective alternatives and the Disease (SAPS-PD) scores compared to placebo [75••].
modest effectiveness of some of these medications, their care-
fully weighed use continues to be a part of expert guidelines Diagnosis and Treatment of Primary Late-Life Psychoses
[61–64]. The neuropsychiatric symptom domains which ap-
pear to improve differentially with antipsychotic treatment are The diagnosis and treatment of primary late-life psychotic
anger, aggression, and paranoid ideation while functional abil- disorders should proceed only after the evaluation for second-
ities, care needs, and quality of life do not seem to improve ary late-life psychotic disorders is complete. Clinicians should
[65]. remember the pre-diagnostic probability in the elderly—three
Recommendations for antipsychotic treatment in the elder- fifths of psychoses are secondary psychoses—and be willing
ly include (ranging from starting dose to maximum target to revisit their assessments as more information becomes
dose) [66, 67••] the following: available.

& Risperidone 0.25 to 1.5 mg daily Depression and Other Affective Disorders with Psychotic
& Olanzapine 2.5 to 10 mg daily Features
& Quetiapine 12.5 to 200 mg daily
& Aripiprazole 2.5 to 12.5 mg daily Major Depressive Disorder

Antidepressant medications have shown promise, particu- Major depressive disorder (MDD) is common in the late life,
larly sertraline and citalopram, for the treatment of behavioral with roughly 4 to 7 % aggregate prevalence in adults 55 years
Curr Psychiatry Rep (2015) 17: 1 Page 7 of 13 1

old and older [76, 77•, 78]. Data from the National Comor- bipolar illness [91]. A majority of cases are diagnosed in the
bidity Survey Replication indicates a 12-month prevalence of second to fifth decades of life, and a second peak occurs at age
2.6% and a lifetime prevalence of 9.8 % in adults 65 years and 65 and over [91]. In elderly inpatients with bipolar disorder,
older [78]. When MDD was combined with minor depression the mean prevalence of late-onset mania was 44 % [91]. Those
and depression treatment status in adults 71 years and older, patients with late-onset bipolar disorder may represent a dis-
overall prevalence of clinically meaningful depressive symp- tinct subset of bipolar disorder [92, 93]. Studies of psychosis
toms rose to 11 % [79]. In the DSM-5, the presence or absence during late-life bipolar disorder are limited and conflicting,
of psychoses is indicated with a diagnostic specifier, “with with one study finding increased depressive episodes with
psychotic features” that may be further detailed using the psychotic features and another finding no difference in the
specifiers “with mood [congruent] psychotic features” or prevalence of psychosis between late-life patients and their
“with mood [incongruent] psychotic features [3••]. younger counterparts [94, 95].
Older persons with MDD are more likely to have psychotic Because of the paucity of treatment studies in this age
features and be resistant to treatment than their younger coun- group, clinical interventions are extrapolated from those of
terparts [80, 81]. Psychotic depression occurs in 20 to 45 % of non-elderly adult bipolar disorder. There is an on-going study
hospitalized elderly depressed patients and 15 % of community- of the treatment of acute mania, treatment of bipolar mania in
dwelling depressed persons. Rates of psychosis do not seem to older adults study (GERI-BD) examining the use of
differ between those elderly subjects with an early-onset (before divalproex and lithium in the elderly [96]. To date, the
age 60) and those with a late-onset (age 60 and above) depres- GERI-BD study has revealed the positive effects of socializa-
sion. Delusions are the most common psychotic symptom in tion on outcomes [97•]. It has also identified ethnicity (non-
late-life depression with psychotic features, and they are most Hispanic Caucasian), symptom severity, and past psychophar-
often mood congruent, e.g., delusions of guilt, delusions of macologic treatments as factors increasing the likelihood of
deserved punishment for moral or personal inadequacies, delu- inpatient psychiatric treatment and a lack of associations be-
sions of nihilism, somatic delusions, and delusions of poverty. tween lifetime bipolar disorder and cognitive decline [98••,
Auditory hallucinations are less common and not easily de- 99]. Another study examining age-group differences in bipo-
scribed by patients, e.g., vague derogatory voices [82]. lar disorder found a higher prevalence of disordered thought
A complete medical workup should be conducted, and content in older adults versus a higher rate of aggression and
alternative psychiatric diagnoses should be ruled out prior to irritability in younger adults [100•].
this diagnosis. The differential diagnoses rely heavily on pa- Sajatovic and Chen’s review of geriatric bipolar disorder
tient and collateral history. Hearing the voices of lost loved provides an excellent summary of the treatment literature
ones is very common in the bereaved elderly and in some cases [101]. To target psychosis occurring in the context of acute
has been reported to be a helpful phenomenon [83]. Once the mania, all the current atypical antipsychotic medications (ex-
diagnosis is established, treatment must be considered. In older cept clozapine) are indicated for use. The olanzapine-
adults, electroconvulsive therapy (ECT) may be most effective fluoxetine combination has strong evidence for its use in
and limit the need for additional pharmacotherapy; however, mixed bipolar patients.
research is necessary before a definitive statement can be made
[84]. In particular, the greater the degree of frailty, the more
likely ECT should be chosen as a first-line treatment [85]. Delusional Disorder and Schizophrenia-Spectrum Illnesses
When ECT is not possible, the best evidence for the phar-
macologic treatment of the psychotically depressed elderly is Schizophrenia
combination therapy of an antidepressant and an antipsychotic
medication. The only RCT that has been published on this An important change in the DSM-5 from previous editions
topic noted the superiority of olanzapine plus sertraline in was the elimination of the subtypes of schizophrenia (para-
obtaining remission in the elderly [86]. Augmentation with noid, disorganized, undifferentiated, residual, and catatonic)
psychotherapy and psychosocial treatments should be consid- due to their “limited diagnostic stability, low reliability, and
ered. Cognitive behavior therapy, problem solving therapy, poor validity” [3••]. Also eliminated were the symptoms that
interpersonal therapy, and supportive therapy are the most established the diagnosis of schizophrenia by their sole pres-
often cited, while CBT is the most studied and has the best ence such as bizarre delusions and Schneiderian hallucina-
evidence for its effectiveness [87]. tions. When establishing the diagnosis of schizophrenia, spe-
cial attention should be paid to differentiating other DSM-5
Bipolar Disorder disorders with psychotic features (major depression, bipolar
disorder, schizoaffective disorder), delusional disorder, and
The prevalence of bipolar disorder in the elderly is estimated personality disorders (schizoid and schizotypal personality
to be between 0.25 and 1 % [88–90]. There are two peaks for disorders).
1 Page 8 of 13 Curr Psychiatry Rep (2015) 17: 1

A review of studies of late-onset schizophrenia found that The clinical features and risks of late-life schizoaffective
approximately 20 to 25 % of patients with schizophrenia were disorder were first discussed in 1971 by Post, who noted their
reported to have experienced the onset of the disorder after age frequent treatment-refractory condition, risk of suicide, and
40, while the remaining four fifths of elderly patients with severe illness [113]. A more recent retrospective chart review
schizophrenia experienced early onset [102, 103]. Today, with confirmed Post’s original findings, further noting an increased
greater numbers of schizophrenia patients surviving into old risk of suicide attempts in depressed versus bipolar-type pa-
age, the prevalence estimates for schizophrenia in adults aged tients greater than 60 years old [114•].
between 45 and 60 are approximately 0.6 to 1 % and 0.1 to
0.5 % in persons aged 65 plus [104–108]. By 2025, about one Delusional Disorder
fourth of persons with schizophrenia will be age 55 and over
[109]. Delusional disorder, according to DSM-5, is diagnosed by the
Although neither the DSM-5 nor ICD-10 distinguishes by presence of one or more delusions for greater than 1 month
age of onset, the International Late-Onset Schizophrenia [3••]. Diagnostic criteria for schizophrenia or schizoaffective
Group proposed that schizophrenia be termed “Late-Onset disorder must not be met. Further classification is made by
Schizophrenia” and “Very Late Onset Schizophrenia-Like subtype of delusion, e.g., erotomanic, grandiose, jealous, per-
Psychosis” for disorders that begin with an onset between secutory, somatic, and mixed.
age 40 and 60 and after the age of 60, respectively [110]. There is a paucity of literature regarding delusional disor-
The former is considered similar to the early-onset disorder ders in the elderly. Studies indicate a prevalence of 0.03 % in
although there is greater preponderance of women. The very the elderly, with women slightly more affected than men
late disorder has features that suggest a neurodegenerative [115]. There are no clear neuroanatomical changes associated
component including more brain abnormalities and neuropsy- with delusional disorder. There is mixed evidence that hearing
chological deficits and is also distinguished from the other two or visual abnormalities might play a role in the development
types by many more females; greater prevalence of persecu- of delusional disorder, with Maher observing that a subset of
tory and partition delusions; higher rates of visual, tactile, and patients develops delusions in the context of sensory
olfactory hallucinations; lower genetic load; more sensory impairment [116].
abnormalities; and the absence of negative symptoms or formal
thought disorder [110]. Treatment
Jeste et al. have described an exaggerated “paradox of ag-
ing” among older adults with schizophrenia [111•]. People There has been a paucity of studies devoted to the pharmaco-
with schizophrenia, when compared to the general population, logical treatment of older adults with schizophrenia. A
have accelerated physical aging, including increased and ear- Cochrane review of antipsychotic medications for elderly peo-
lier medical comorbidity and mortality; however, their cogni- ple (age 65+) with schizophrenia found only three RCTs in-
tive aging rate remains normal following an initial, persistent volving 252 persons. One involved drugs that are no longer
occurrence of mild neurocognitive disorder [112]. Conversely, available. The other studies found no differences between ris-
as these patients age, psychosocial function improves, psycho- peridone and olanzapine and olanzapine and haloperidol
sis decreases, relapse and hospitalization rates decrease, self- [117].
management improves, and they experience an improvement Evidence-based treatment of late-onset schizophrenia is
in their quality of well-being [112]. based primarily on findings of early-onset individuals who
survived into later life. The most recent Cochrane review
Schizoaffective Disorder conducted in 2012 found no “good quality” data to support
the use of antipsychotic medications in the late-onset or very
With the publication of DSM-5, the diagnosis of late-onset schizophrenia [118]. One trial was found “accept-
schizoaffective disorder was reformulated as a longitudinal able,” a controlled study of risperidone and olanzapine, but
condition, more in keeping with other major psychiatric dis- did not provide enough usable data to make conclusions [118,
orders [3••]. The diagnosis now requires the presence of a 119].
major mood component during the “majority” of the lifetime On the other hand, there is considerable clinical experience
duration of illness rather than only episodically as in DSM-IV- using risperidone, olanzapine, aripiprazole, and clozapine for
TR. The diagnosis is established once an uninterrupted period the treatment of late-life schizophrenia [28, 52••, 119]. Con-
of illness includes a major mood episode concurrently with sensus guidelines currently recommended for schizophrenia
schizophrenia criteria. Delusions or hallucinations must occur in older adults are as follows [28]:
in the absence of a mood episode for at least 2 weeks at any
point during the course of the illness. The disorder is further & First line: risperidone 1.25 to 3.5 mg/day
classified into bipolar and depressed types. & Quetiapine 100 to 300 mg/day
Curr Psychiatry Rep (2015) 17: 1 Page 9 of 13 1

& Olanzapine 7.5 to 15 mg/day careful evaluation. There are no reliable pathognomonic signs
& Aripiprazole 15 to 30 mg/day to distinguish primary or secondary psychosis. Primary psy-
chosis is a diagnosis of exclusion, and the clinician must rule
Starting dosages for late-onset persons should be at 25 % of out secondary causes. Roughly three out of five older patients
the recommended adult dose and maintenance doses at 25– with newly incident psychosis have secondary psychoses.
50 % of the adult dose. Often, effective doses for early onset Thus, every new-onset psychoses or appreciable change in
can be 50–75 % of younger patients. symptoms necessitates a medical workup. It is useful to re-
There are few specific treatment studies of late-life member the “six d’s” of late-life psychosis (Table 1) in formu-
schizoaffective disorder, and most include this group with lating a differential diagnosis and the acronym “MINE” to
the treatment of late-life schizophrenia [118]. As noted above, trigger a list of potential medical diagnoses associated with
a cautious approach is recommended with the smallest effec- secondary psychosis (Table 2).
tive dosage of antipsychotic medication with adjunctive treat- Treatment is geared towards the specific cause of psychosis
ment based on their subtype of illness and according to the and tailored based on comorbid conditions. Frequently, environ-
consensus guidelines for adults. Mood-stabilizing medica- mental and psychosocial interventions are first-line treatments in
tions (lithium, divalproex, carbamazepine, lamotrigine) and late-life psychoses. Caution should be exercised in all elderly
antidepressants should be used judiciously and in the mini- patients when initiating pharmacotherapy for psychosis, particu-
mum effective dosages. larly antipsychotic medications because of their association with
There are no available studies on the treatment of late-life increased morbidity and mortality. Each additional pharmaco-
delusional disorder. Expert consensus guidelines recommend logic agent adds to the medication burden for elderly patients
the use of atypical antipsychotic medications as follows [28, already at risk for adverse events because of polypharmacy.
52••]: Finally, there is a remarkable gap between the prevalence
of psychotic disorders in older adults and the availability of
& First line: risperidone 0.75–2.5 mg/day evidence-based treatment. The dramatic growth in the elderly
& Olanzapine 5–10 mg/day population over the first half of this century creates a compel-
& Quetiapine 50–200 mg/day ling need to address this gap.

The adage of geriatric psychiatry, “start low, go slow,” Compliance with Ethics Guidelines
should be heeded when initiating antipsychotic treatment. El-
ders are prone to adverse effects including cardiovascular, Conflict of Interest Michael M. Reinhardt has received a training grant
from the Health Resources and Services Administration.
metabolic, sedation, anticholinergic burden, extrapyramidal Carl I. Cohen receives funding from the Health Resources and Ser-
symptoms, tardive dyskinesia, orthostatic hypotension, meta- vices Administration and the State University of New York Health Net-
bolic changes, falls, hyperprolactinemia, agranulocytosis, and work of Excellence.
neuroleptic malignant syndrome [52••, 120]. To ensure their
safety, patients should be monitored regularly with a complete Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
blood count, comprehensive metabolic panel, lipid panel, he- of the authors.
moglobin A1C, electrocardiogram, orthostatic vital signs, ab-
normal involuntary movement scale, and weight checks.
Psychosocial treatments should be used adjunctively to References
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