Late-life psychosis: It’s efficacy vs. cost in the tug-of-war over treatment

As psychiatrists, we are being pulled in opposite directions between conflicting goals: to reduce health care costs and to provide our patients with the sophistication and specificity of newly available—and more expensive—biological therapies. In the treatment of late-life psychosis, the evidence is impressive and persuasive that atypical antipsychotic drugs are worth the investment.

Atypical antipsychotics should usually be considered first-line therapy for late-life psychosis, though they cost more than the older neuroleptics. Overall, drugs comprise a minor portion of the cost of treating psychosis but may have a major impact on outcomes.¹ With their safer side effect profile, the atypicals have enabled many patients with schizophrenia to “reintegrate” and become contributing members of society. Likewise, the use of atypicals can allow older patients with psychotic symptoms to function longer and more productively in their homes and communities.

Table 1

DIFFERENCES BETWEEN LATE-AND EARLY-ONSET SCHIZOPHRENIA

Without appropriate treatment of psychosis in younger patients, we know that recurrences and relapses can cause demonstrable brain changes and lead to residual symptoms.² Older patients have been shown to lose 0.2 “well years” for every year they have psychotic symptoms.³

One illness or many?

Psychotic symptoms can occur in late life for a variety of reasons, and each diagnosis has different implications for patient work-up and treatment. Causes of psychosis in older patients include late-onset schizophrenia, dementia, affective disorder, delusional disorder, and delirium.

Late-life schizophrenia As life expectancy increases, schizophrenia is increasingly being diagnosed in older persons. In a sample of hospitalized patients with schizophrenia, onset of illness occurred after age 50 in 13%, after age 60 in 7%, and after age 70 in 3%.⁴ The clinical features of schizophrenia may be modified by the concurrent development of dementia. Thus, this reported increase in psychosis after age 50 may be secondary to an increased incidence of dementia, Parkinson’s disease, cerebrovascular events, and neoplasms.

Early definitions of “paraphrenia” and later schizophrenia described delusions and hallucinations that developed without disturbance of affect, with onset in early adult life.⁵ The occurrence of disorganized behavior and thinking in late life was ascribed to the effects of “senility” or other organic factors.

In 1943, Bleuler⁶ reported on a series of 126 patients in whom psychosis developed after age 40. In this group, the illness began after age 60 in 4%.

Current diagnostic criteria for schizophrenia do not exclude or categorize individuals on the basis of age. DSMIV does acknowledge a subgroup of patients with “late-onset” schizophrenia after age 45. However, there are important clinical differences in the presentations of the early- and late-onset types (Table 1). For example, even after adjusting for the greater longevity of women, more women than men develop late-onset schizophrenia. Also, compared with the early-onset type, in late-life schizophrenia:

• Premorbid paranoid or schizoid personality traits appear to be much less prominent.
• Patients may have had better occupational functioning and are more likely to have been married.
• Negative symptoms tend to be less severe, although they do contribute to functional decline.

Visual and hearing loss are among the risk factors correlated with late-onset schizophrenia.⁷ Sensory loss isolates an older person and leads to misinterpretation and misidentification of environmental cues. Other risk factors, in addition to female gender, include cognitive loss, poor social supports, living alone, and alcohol or drug abuse.

Dementia Between 20 and 50% of patients with vascular and mixed dementias exhibit psychotic symptoms.⁸ Among those with Alzheimer’s dementia, 30% exhibit persecutory delusions.⁹ Adding to this population are persons with early-onset schizophrenia, who are living longer and can also develop dementia.

While neuroimaging can sometimes aid in diagnosis, abnormalities seen on neuroimaging of patients with psychotic symptoms do not necessarily correlate with cognitive deficits. The clinical significance of these findings is unclear.^10,11 Because of differences in therapy, it is important to establish whether the primary diagnosis is dementia or schizophrenia (Table 2).

Affective psychoses Late-life depression and mania are often unrecognized because of atypical presentations. In the elderly, depression may present with withdrawal, mood-incongruent delusions,¹² and symptoms that mimic medical illness. Older manic patients may be misidentified as intrusive, hypersexual, or agitated. A high suspicion index, carefully elicited family history, and past psychiatric illness in the patient usually can clarify the diagnosis.

Delusional disorder Suspiciousness and paranoia are common findings in late life, with an estimated prevalence of 4 to 6% in the older population. Patients with delusional disorder show little evidence of cognitive deficits and—unlike those with schizophrenia—continue to maintain a high level of function.¹³ Delusions are nonbizarre and well systematized, and hallucinations are not a prominent feature.

Delirium Older persons are particularly vulnerable to developing delirium. Common causes include urinary tract infection, bowel impaction, heart failure, endocrinopathies, and drug toxicity caused by prescribed or over-the-counter drugs. CNS conditions such as subdural hematoma, cerebrovascular accident, slow-growing intracranial tumors, and encephalitis can be associated with the development of hallucinations and delusions without clouding consciousness.

While an agitated, hallucinating patient with clearly evident fluctuations in the sensorium may be readily diagnosed with a delirium, patients who are quiet, withdrawn, and apathetic may be less easy to recognize. Clinicians should therefore be vigilant for both the hyperkinetic and hypokinetic presentations of delirium when assessing older patients.

Work-up

When psychotic symptoms present for the first time in late life, medical causes must be ruled out first. A detailed history, including collateral information from other sources, includes:

• premorbid function
• psychiatric history, including history of affective illness
• family history of schizophrenia, affective illness, and Alzheimer’s disease
• medical history, including risks for cerebrovascular disease.

The examination should include a complete medical and neurologic evaluation, giving special attention to sensory loss, prescribed and over-the-counter drugs, recent changes in drug regimen, and cognitive screening. Laboratory work-up includes:

• in all cases: CBC/differential, BUN, TFT, B₁₂/folate, and RPR
• in selected cases: MRI, HIV screening, toxicology screen, neuropsychological testing
• in rare cases: lumbar puncture, PET or SPECT imaging.

If the suggested work-up leads to diagnosis of medical illness, begin appropriate treatment. Behavioral symptoms during medical illness, such as with delirium, may require concurrent psychotropic medication until the medical illness is controlled.

If the medical work-up is negative, the clinician then needs to make the appropriate psychiatric diagnosis and institute antipsychotic treatment as indicated.

Table 2

CLINICAL DIFFERENCES BETWEEN DEMENTIA AND SCHIZOPHRENIA

Table 3

USE OF ATYPICAL ANTIPSYCHOTICS IN OLDER PATIENTS

Prescribing antipsychotics

Prescribing psychoactive medications for older patients is similar to pediatric prescribing. You need to distinguish between behaviors that are “disturbed” as a result of a psychotic process or “disturbing,” for which behavioral interventions may be more appropriate. In any case, pharmacologic and behavioral interventions are used concurrently.

When prescribing for older patients, consider the possible interaction of comorbid medical conditions and altered pharmacokinetics and pharmacodynamics, which increase the potential for drug-drug interactions. Start low and go slow to minimize the potential for adverse side effects and to ensure optimal preservation of function.

In general, atypical antipsychotics are considered first-line therapy, unless there is a compelling reason not to use them in an individual patient. Conventional neuroleptic antipsychotics carry a much higher risk of adverse drug reactions and functional loss without providing substantially greater efficacy.¹⁴ Atypical antipsychotics differ not only from the older neuroleptics but also from each other—including their safety profiles for use in older patients (Table 3).

Clozapine is a dibenzodiazepine that is indicated for treatment-resistant schizophrenia. The first atypical antipsychotic, clozapine significantly reduced the incidence of extrapyramidal symptoms (EPS) seen with the neuroleptic antipsychotics. Clozapine also was effective against the “negative” symptoms of schizophrenia such as apathy, anhedonia, and emotional blunting, which severely limited the ability of patients with schizophrenia to function in society.

The limitations of clozapine include its potential to cause agranulocytosis and the requirement for weekly blood tests. It is also fairly sedating. A number of reports have suggested a link between the use of clozapine and the development of type 2 diabetes, hyperglycemia, and pancreatitis.^15,16 Earlier this year, the FDA issued a “black box” warning linking the use of clozapine with myocarditis. For all of these reasons, clozapine is not recommended for use in older patients.

Risperidone is a benzisoxazole derivative indicated for treatment of psychotic disorders. Risperidone’s antipsychotic efficacy is equivalent to that of haloperidol, but it has a much safer side-effect profile. In one multicenter study comparing risperidone and a placebo at single daily dosages of 0.5, 1.0, and 2.0 mg, risperidone was found to be effective in controlling the psychosis and behavioral disturbance associated with dementia. The authors recommended using a dosage of 1.0 mg/d because higher dosages resulted in excessive sedation and EPS.¹⁷

Risk of side effects is dose-dependent, especially in the older patient. Risperidone is the only atypical antipsychotic associated with persistent hyperprolactinemia, which may indirectly contribute to increased osteoporosis and atherogenesis.^18,19 Orthostatic hypotension, especially with initial dosages greater than 1.5 mg/d and rapid dose escalation (≥ 25% every 24 to 48 hours), may also limit its use in older patients.

Olanzapine is a thiobenzodiazepine derivative indicated for treatment of psychosis and acute bipolar mania. Olanzapine has a receptor profile that is somewhat analogous with that of clozapine. Its antipsychotic efficacy is equivalent to that of risperidone, but it has a more favorable safety profile. Like risperidone, olanzapine is relatively nonsedating, but it is significantly less likely to cause EPS and orthostatic hypotension, and its use is not associated with persistent hyperprolactinemia.

Based on its vitro muscarinic receptor antagonism profile, some clinicians incorrectly assume that olanzapine is highly anticholinergic. In vivo data and clinical experience have not borne out this contention.^20,21 Weight gain with olanzapine is relatively infrequent in older persons. A rapid-dissolve preparation can be useful in resistant and noncompliant patients. An IM preparation has been approved by the FDA but has not yet been made available by the manufacturer.

Quetiapine is a dibenzothiazepine derivative indicated for treatment of psychotic disorders. Despite limited data on its efficacy in late-life psychosis, clinical experience would suggest that its antipsychotic efficacy would at least equal that of other drugs in this category.

The need for twice-daily dosing and titration to a therapeutic response can sometimes limit the use of quetiapine. Sedation can be a problem at dosages greater than 200 mg/d. Because quetiapine has a relatively lower potential among the antipsychotics to cause EPS, it may be a first-line choice in patients with Parkinson’s disease and Lewy body dementia.

Ziprasidone is a benzothiazolylpiperazine indicated for treatment of psychosis. Experience with its use in older patients is limited. Ziprasidone should be avoided in patients with significant cardiovascular disease because of its potential to cause QT prolongation and cardiac arrhythmias. Although rare, this cardiac side effect may be life-threatening, and clinicians must be exceptionally vigilant when using ziprasidone in older patients. Risk factors for QT prolongation include older age, female sex, pre-existing cardiac disease, hypokalemia, and hypomagnesemia.

Ziprasidone can be somewhat sedating. An IM preparation is under development but has not been approved for use by the FDA

Neuroleptics and other options

Occasionally a typical neuroleptic may be the most appropriate first-line drug for older patients with psychotic symptoms. For example, a mid-potency neuroleptic such as perphenazine at an IM dose of 2 to 4 mg may be considered when severe agitation and aggression pose a substantial safety risk for the patient or caregiver and require rapid control. Haloperidol, despite its widespread use in both acute and long-term settings, should be used with caution because it has great potential for causing EPS and can immobilize an older patient, resulting in further functional decline. Regardless of which typical neuroleptic is used, switch the patient to an atypical antipsychotic as soon as agitation is under control.

Antidepressants Affective psychoses in older patients may require the addition of an antidepressant to the antipsychotic drug. The selective serotonin reuptake inhibitors fluoxetine and sertraline have proven track records for efficacy and safety and should be considered first-line agents.

Other options Electroconvulsive therapy is safe and effective for older patients with psychotic depression or late-life mania. Late-life mania also may respond well to the anticonvulsant divalproex sodium. Avoid anxiolytics in older patients because of the potential of these agents to cause sedation or disinhibition and their associated risk of falls and confusion. Buspirone in higher dosages (40 to 60 mg/d) can sometimes help manage chronic anxiety states.

Related resource

• Sadavoy J, Lazarus LW, Jarvik LF, Grossman GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.

Drug brand names

• Buspirone • Buspar
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Snow reports no affiliation or financial arrangement with any of the companies whose products are mentioned in this article.

Dr. Verma reports that he is on the speakers’ bureau of Eli Lilly and Co. and Abbott Laboratories, serves as a consultant to Eli Lilly and Co., and receives grant support from Eli Lilly and Co. and GlaxoSmithKline.

As psychiatrists, we are being pulled in opposite directions between conflicting goals: to reduce health care costs and to provide our patients with the sophistication and specificity of newly available—and more expensive—biological therapies. In the treatment of late-life psychosis, the evidence is impressive and persuasive that atypical antipsychotic drugs are worth the investment.

Atypical antipsychotics should usually be considered first-line therapy for late-life psychosis, though they cost more than the older neuroleptics. Overall, drugs comprise a minor portion of the cost of treating psychosis but may have a major impact on outcomes.¹ With their safer side effect profile, the atypicals have enabled many patients with schizophrenia to “reintegrate” and become contributing members of society. Likewise, the use of atypicals can allow older patients with psychotic symptoms to function longer and more productively in their homes and communities.

Table 1

DIFFERENCES BETWEEN LATE-AND EARLY-ONSET SCHIZOPHRENIA

Without appropriate treatment of psychosis in younger patients, we know that recurrences and relapses can cause demonstrable brain changes and lead to residual symptoms.² Older patients have been shown to lose 0.2 “well years” for every year they have psychotic symptoms.³

One illness or many?

Psychotic symptoms can occur in late life for a variety of reasons, and each diagnosis has different implications for patient work-up and treatment. Causes of psychosis in older patients include late-onset schizophrenia, dementia, affective disorder, delusional disorder, and delirium.

Late-life schizophrenia As life expectancy increases, schizophrenia is increasingly being diagnosed in older persons. In a sample of hospitalized patients with schizophrenia, onset of illness occurred after age 50 in 13%, after age 60 in 7%, and after age 70 in 3%.⁴ The clinical features of schizophrenia may be modified by the concurrent development of dementia. Thus, this reported increase in psychosis after age 50 may be secondary to an increased incidence of dementia, Parkinson’s disease, cerebrovascular events, and neoplasms.

Early definitions of “paraphrenia” and later schizophrenia described delusions and hallucinations that developed without disturbance of affect, with onset in early adult life.⁵ The occurrence of disorganized behavior and thinking in late life was ascribed to the effects of “senility” or other organic factors.

In 1943, Bleuler⁶ reported on a series of 126 patients in whom psychosis developed after age 40. In this group, the illness began after age 60 in 4%.

Current diagnostic criteria for schizophrenia do not exclude or categorize individuals on the basis of age. DSMIV does acknowledge a subgroup of patients with “late-onset” schizophrenia after age 45. However, there are important clinical differences in the presentations of the early- and late-onset types (Table 1). For example, even after adjusting for the greater longevity of women, more women than men develop late-onset schizophrenia. Also, compared with the early-onset type, in late-life schizophrenia:

• Premorbid paranoid or schizoid personality traits appear to be much less prominent.
• Patients may have had better occupational functioning and are more likely to have been married.
• Negative symptoms tend to be less severe, although they do contribute to functional decline.

Visual and hearing loss are among the risk factors correlated with late-onset schizophrenia.⁷ Sensory loss isolates an older person and leads to misinterpretation and misidentification of environmental cues. Other risk factors, in addition to female gender, include cognitive loss, poor social supports, living alone, and alcohol or drug abuse.

Dementia Between 20 and 50% of patients with vascular and mixed dementias exhibit psychotic symptoms.⁸ Among those with Alzheimer’s dementia, 30% exhibit persecutory delusions.⁹ Adding to this population are persons with early-onset schizophrenia, who are living longer and can also develop dementia.

While neuroimaging can sometimes aid in diagnosis, abnormalities seen on neuroimaging of patients with psychotic symptoms do not necessarily correlate with cognitive deficits. The clinical significance of these findings is unclear.^10,11 Because of differences in therapy, it is important to establish whether the primary diagnosis is dementia or schizophrenia (Table 2).

Affective psychoses Late-life depression and mania are often unrecognized because of atypical presentations. In the elderly, depression may present with withdrawal, mood-incongruent delusions,¹² and symptoms that mimic medical illness. Older manic patients may be misidentified as intrusive, hypersexual, or agitated. A high suspicion index, carefully elicited family history, and past psychiatric illness in the patient usually can clarify the diagnosis.

Delusional disorder Suspiciousness and paranoia are common findings in late life, with an estimated prevalence of 4 to 6% in the older population. Patients with delusional disorder show little evidence of cognitive deficits and—unlike those with schizophrenia—continue to maintain a high level of function.¹³ Delusions are nonbizarre and well systematized, and hallucinations are not a prominent feature.

Delirium Older persons are particularly vulnerable to developing delirium. Common causes include urinary tract infection, bowel impaction, heart failure, endocrinopathies, and drug toxicity caused by prescribed or over-the-counter drugs. CNS conditions such as subdural hematoma, cerebrovascular accident, slow-growing intracranial tumors, and encephalitis can be associated with the development of hallucinations and delusions without clouding consciousness.

While an agitated, hallucinating patient with clearly evident fluctuations in the sensorium may be readily diagnosed with a delirium, patients who are quiet, withdrawn, and apathetic may be less easy to recognize. Clinicians should therefore be vigilant for both the hyperkinetic and hypokinetic presentations of delirium when assessing older patients.

Work-up

When psychotic symptoms present for the first time in late life, medical causes must be ruled out first. A detailed history, including collateral information from other sources, includes:

• premorbid function
• psychiatric history, including history of affective illness
• family history of schizophrenia, affective illness, and Alzheimer’s disease
• medical history, including risks for cerebrovascular disease.

The examination should include a complete medical and neurologic evaluation, giving special attention to sensory loss, prescribed and over-the-counter drugs, recent changes in drug regimen, and cognitive screening. Laboratory work-up includes:

• in all cases: CBC/differential, BUN, TFT, B₁₂/folate, and RPR
• in selected cases: MRI, HIV screening, toxicology screen, neuropsychological testing
• in rare cases: lumbar puncture, PET or SPECT imaging.

If the suggested work-up leads to diagnosis of medical illness, begin appropriate treatment. Behavioral symptoms during medical illness, such as with delirium, may require concurrent psychotropic medication until the medical illness is controlled.

If the medical work-up is negative, the clinician then needs to make the appropriate psychiatric diagnosis and institute antipsychotic treatment as indicated.

Table 2

CLINICAL DIFFERENCES BETWEEN DEMENTIA AND SCHIZOPHRENIA

Table 3

USE OF ATYPICAL ANTIPSYCHOTICS IN OLDER PATIENTS

Prescribing antipsychotics

Prescribing psychoactive medications for older patients is similar to pediatric prescribing. You need to distinguish between behaviors that are “disturbed” as a result of a psychotic process or “disturbing,” for which behavioral interventions may be more appropriate. In any case, pharmacologic and behavioral interventions are used concurrently.

When prescribing for older patients, consider the possible interaction of comorbid medical conditions and altered pharmacokinetics and pharmacodynamics, which increase the potential for drug-drug interactions. Start low and go slow to minimize the potential for adverse side effects and to ensure optimal preservation of function.

In general, atypical antipsychotics are considered first-line therapy, unless there is a compelling reason not to use them in an individual patient. Conventional neuroleptic antipsychotics carry a much higher risk of adverse drug reactions and functional loss without providing substantially greater efficacy.¹⁴ Atypical antipsychotics differ not only from the older neuroleptics but also from each other—including their safety profiles for use in older patients (Table 3).

Clozapine is a dibenzodiazepine that is indicated for treatment-resistant schizophrenia. The first atypical antipsychotic, clozapine significantly reduced the incidence of extrapyramidal symptoms (EPS) seen with the neuroleptic antipsychotics. Clozapine also was effective against the “negative” symptoms of schizophrenia such as apathy, anhedonia, and emotional blunting, which severely limited the ability of patients with schizophrenia to function in society.

The limitations of clozapine include its potential to cause agranulocytosis and the requirement for weekly blood tests. It is also fairly sedating. A number of reports have suggested a link between the use of clozapine and the development of type 2 diabetes, hyperglycemia, and pancreatitis.^15,16 Earlier this year, the FDA issued a “black box” warning linking the use of clozapine with myocarditis. For all of these reasons, clozapine is not recommended for use in older patients.

Risperidone is a benzisoxazole derivative indicated for treatment of psychotic disorders. Risperidone’s antipsychotic efficacy is equivalent to that of haloperidol, but it has a much safer side-effect profile. In one multicenter study comparing risperidone and a placebo at single daily dosages of 0.5, 1.0, and 2.0 mg, risperidone was found to be effective in controlling the psychosis and behavioral disturbance associated with dementia. The authors recommended using a dosage of 1.0 mg/d because higher dosages resulted in excessive sedation and EPS.¹⁷

Risk of side effects is dose-dependent, especially in the older patient. Risperidone is the only atypical antipsychotic associated with persistent hyperprolactinemia, which may indirectly contribute to increased osteoporosis and atherogenesis.^18,19 Orthostatic hypotension, especially with initial dosages greater than 1.5 mg/d and rapid dose escalation (≥ 25% every 24 to 48 hours), may also limit its use in older patients.

Olanzapine is a thiobenzodiazepine derivative indicated for treatment of psychosis and acute bipolar mania. Olanzapine has a receptor profile that is somewhat analogous with that of clozapine. Its antipsychotic efficacy is equivalent to that of risperidone, but it has a more favorable safety profile. Like risperidone, olanzapine is relatively nonsedating, but it is significantly less likely to cause EPS and orthostatic hypotension, and its use is not associated with persistent hyperprolactinemia.

Based on its vitro muscarinic receptor antagonism profile, some clinicians incorrectly assume that olanzapine is highly anticholinergic. In vivo data and clinical experience have not borne out this contention.^20,21 Weight gain with olanzapine is relatively infrequent in older persons. A rapid-dissolve preparation can be useful in resistant and noncompliant patients. An IM preparation has been approved by the FDA but has not yet been made available by the manufacturer.

Quetiapine is a dibenzothiazepine derivative indicated for treatment of psychotic disorders. Despite limited data on its efficacy in late-life psychosis, clinical experience would suggest that its antipsychotic efficacy would at least equal that of other drugs in this category.

The need for twice-daily dosing and titration to a therapeutic response can sometimes limit the use of quetiapine. Sedation can be a problem at dosages greater than 200 mg/d. Because quetiapine has a relatively lower potential among the antipsychotics to cause EPS, it may be a first-line choice in patients with Parkinson’s disease and Lewy body dementia.

Ziprasidone is a benzothiazolylpiperazine indicated for treatment of psychosis. Experience with its use in older patients is limited. Ziprasidone should be avoided in patients with significant cardiovascular disease because of its potential to cause QT prolongation and cardiac arrhythmias. Although rare, this cardiac side effect may be life-threatening, and clinicians must be exceptionally vigilant when using ziprasidone in older patients. Risk factors for QT prolongation include older age, female sex, pre-existing cardiac disease, hypokalemia, and hypomagnesemia.

Ziprasidone can be somewhat sedating. An IM preparation is under development but has not been approved for use by the FDA

Neuroleptics and other options

Occasionally a typical neuroleptic may be the most appropriate first-line drug for older patients with psychotic symptoms. For example, a mid-potency neuroleptic such as perphenazine at an IM dose of 2 to 4 mg may be considered when severe agitation and aggression pose a substantial safety risk for the patient or caregiver and require rapid control. Haloperidol, despite its widespread use in both acute and long-term settings, should be used with caution because it has great potential for causing EPS and can immobilize an older patient, resulting in further functional decline. Regardless of which typical neuroleptic is used, switch the patient to an atypical antipsychotic as soon as agitation is under control.

Antidepressants Affective psychoses in older patients may require the addition of an antidepressant to the antipsychotic drug. The selective serotonin reuptake inhibitors fluoxetine and sertraline have proven track records for efficacy and safety and should be considered first-line agents.

Other options Electroconvulsive therapy is safe and effective for older patients with psychotic depression or late-life mania. Late-life mania also may respond well to the anticonvulsant divalproex sodium. Avoid anxiolytics in older patients because of the potential of these agents to cause sedation or disinhibition and their associated risk of falls and confusion. Buspirone in higher dosages (40 to 60 mg/d) can sometimes help manage chronic anxiety states.

Related resource

• Sadavoy J, Lazarus LW, Jarvik LF, Grossman GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.

Drug brand names

• Buspirone • Buspar
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Snow reports no affiliation or financial arrangement with any of the companies whose products are mentioned in this article.

Dr. Verma reports that he is on the speakers’ bureau of Eli Lilly and Co. and Abbott Laboratories, serves as a consultant to Eli Lilly and Co., and receives grant support from Eli Lilly and Co. and GlaxoSmithKline.

As psychiatrists, we are being pulled in opposite directions between conflicting goals: to reduce health care costs and to provide our patients with the sophistication and specificity of newly available—and more expensive—biological therapies. In the treatment of late-life psychosis, the evidence is impressive and persuasive that atypical antipsychotic drugs are worth the investment.

Atypical antipsychotics should usually be considered first-line therapy for late-life psychosis, though they cost more than the older neuroleptics. Overall, drugs comprise a minor portion of the cost of treating psychosis but may have a major impact on outcomes.¹ With their safer side effect profile, the atypicals have enabled many patients with schizophrenia to “reintegrate” and become contributing members of society. Likewise, the use of atypicals can allow older patients with psychotic symptoms to function longer and more productively in their homes and communities.

Table 1

DIFFERENCES BETWEEN LATE-AND EARLY-ONSET SCHIZOPHRENIA

Without appropriate treatment of psychosis in younger patients, we know that recurrences and relapses can cause demonstrable brain changes and lead to residual symptoms.² Older patients have been shown to lose 0.2 “well years” for every year they have psychotic symptoms.³

One illness or many?

Psychotic symptoms can occur in late life for a variety of reasons, and each diagnosis has different implications for patient work-up and treatment. Causes of psychosis in older patients include late-onset schizophrenia, dementia, affective disorder, delusional disorder, and delirium.

Late-life schizophrenia As life expectancy increases, schizophrenia is increasingly being diagnosed in older persons. In a sample of hospitalized patients with schizophrenia, onset of illness occurred after age 50 in 13%, after age 60 in 7%, and after age 70 in 3%.⁴ The clinical features of schizophrenia may be modified by the concurrent development of dementia. Thus, this reported increase in psychosis after age 50 may be secondary to an increased incidence of dementia, Parkinson’s disease, cerebrovascular events, and neoplasms.

Early definitions of “paraphrenia” and later schizophrenia described delusions and hallucinations that developed without disturbance of affect, with onset in early adult life.⁵ The occurrence of disorganized behavior and thinking in late life was ascribed to the effects of “senility” or other organic factors.

In 1943, Bleuler⁶ reported on a series of 126 patients in whom psychosis developed after age 40. In this group, the illness began after age 60 in 4%.

Current diagnostic criteria for schizophrenia do not exclude or categorize individuals on the basis of age. DSMIV does acknowledge a subgroup of patients with “late-onset” schizophrenia after age 45. However, there are important clinical differences in the presentations of the early- and late-onset types (Table 1). For example, even after adjusting for the greater longevity of women, more women than men develop late-onset schizophrenia. Also, compared with the early-onset type, in late-life schizophrenia:

• Premorbid paranoid or schizoid personality traits appear to be much less prominent.
• Patients may have had better occupational functioning and are more likely to have been married.
• Negative symptoms tend to be less severe, although they do contribute to functional decline.

Visual and hearing loss are among the risk factors correlated with late-onset schizophrenia.⁷ Sensory loss isolates an older person and leads to misinterpretation and misidentification of environmental cues. Other risk factors, in addition to female gender, include cognitive loss, poor social supports, living alone, and alcohol or drug abuse.

Dementia Between 20 and 50% of patients with vascular and mixed dementias exhibit psychotic symptoms.⁸ Among those with Alzheimer’s dementia, 30% exhibit persecutory delusions.⁹ Adding to this population are persons with early-onset schizophrenia, who are living longer and can also develop dementia.

While neuroimaging can sometimes aid in diagnosis, abnormalities seen on neuroimaging of patients with psychotic symptoms do not necessarily correlate with cognitive deficits. The clinical significance of these findings is unclear.^10,11 Because of differences in therapy, it is important to establish whether the primary diagnosis is dementia or schizophrenia (Table 2).

Affective psychoses Late-life depression and mania are often unrecognized because of atypical presentations. In the elderly, depression may present with withdrawal, mood-incongruent delusions,¹² and symptoms that mimic medical illness. Older manic patients may be misidentified as intrusive, hypersexual, or agitated. A high suspicion index, carefully elicited family history, and past psychiatric illness in the patient usually can clarify the diagnosis.

Delusional disorder Suspiciousness and paranoia are common findings in late life, with an estimated prevalence of 4 to 6% in the older population. Patients with delusional disorder show little evidence of cognitive deficits and—unlike those with schizophrenia—continue to maintain a high level of function.¹³ Delusions are nonbizarre and well systematized, and hallucinations are not a prominent feature.

Delirium Older persons are particularly vulnerable to developing delirium. Common causes include urinary tract infection, bowel impaction, heart failure, endocrinopathies, and drug toxicity caused by prescribed or over-the-counter drugs. CNS conditions such as subdural hematoma, cerebrovascular accident, slow-growing intracranial tumors, and encephalitis can be associated with the development of hallucinations and delusions without clouding consciousness.

While an agitated, hallucinating patient with clearly evident fluctuations in the sensorium may be readily diagnosed with a delirium, patients who are quiet, withdrawn, and apathetic may be less easy to recognize. Clinicians should therefore be vigilant for both the hyperkinetic and hypokinetic presentations of delirium when assessing older patients.

Work-up

When psychotic symptoms present for the first time in late life, medical causes must be ruled out first. A detailed history, including collateral information from other sources, includes:

• premorbid function
• psychiatric history, including history of affective illness
• family history of schizophrenia, affective illness, and Alzheimer’s disease
• medical history, including risks for cerebrovascular disease.

The examination should include a complete medical and neurologic evaluation, giving special attention to sensory loss, prescribed and over-the-counter drugs, recent changes in drug regimen, and cognitive screening. Laboratory work-up includes:

• in all cases: CBC/differential, BUN, TFT, B₁₂/folate, and RPR
• in selected cases: MRI, HIV screening, toxicology screen, neuropsychological testing
• in rare cases: lumbar puncture, PET or SPECT imaging.

If the suggested work-up leads to diagnosis of medical illness, begin appropriate treatment. Behavioral symptoms during medical illness, such as with delirium, may require concurrent psychotropic medication until the medical illness is controlled.

If the medical work-up is negative, the clinician then needs to make the appropriate psychiatric diagnosis and institute antipsychotic treatment as indicated.

Table 2

CLINICAL DIFFERENCES BETWEEN DEMENTIA AND SCHIZOPHRENIA

Table 3

USE OF ATYPICAL ANTIPSYCHOTICS IN OLDER PATIENTS

Prescribing antipsychotics

Prescribing psychoactive medications for older patients is similar to pediatric prescribing. You need to distinguish between behaviors that are “disturbed” as a result of a psychotic process or “disturbing,” for which behavioral interventions may be more appropriate. In any case, pharmacologic and behavioral interventions are used concurrently.

When prescribing for older patients, consider the possible interaction of comorbid medical conditions and altered pharmacokinetics and pharmacodynamics, which increase the potential for drug-drug interactions. Start low and go slow to minimize the potential for adverse side effects and to ensure optimal preservation of function.

In general, atypical antipsychotics are considered first-line therapy, unless there is a compelling reason not to use them in an individual patient. Conventional neuroleptic antipsychotics carry a much higher risk of adverse drug reactions and functional loss without providing substantially greater efficacy.¹⁴ Atypical antipsychotics differ not only from the older neuroleptics but also from each other—including their safety profiles for use in older patients (Table 3).

Clozapine is a dibenzodiazepine that is indicated for treatment-resistant schizophrenia. The first atypical antipsychotic, clozapine significantly reduced the incidence of extrapyramidal symptoms (EPS) seen with the neuroleptic antipsychotics. Clozapine also was effective against the “negative” symptoms of schizophrenia such as apathy, anhedonia, and emotional blunting, which severely limited the ability of patients with schizophrenia to function in society.

The limitations of clozapine include its potential to cause agranulocytosis and the requirement for weekly blood tests. It is also fairly sedating. A number of reports have suggested a link between the use of clozapine and the development of type 2 diabetes, hyperglycemia, and pancreatitis.^15,16 Earlier this year, the FDA issued a “black box” warning linking the use of clozapine with myocarditis. For all of these reasons, clozapine is not recommended for use in older patients.

Risperidone is a benzisoxazole derivative indicated for treatment of psychotic disorders. Risperidone’s antipsychotic efficacy is equivalent to that of haloperidol, but it has a much safer side-effect profile. In one multicenter study comparing risperidone and a placebo at single daily dosages of 0.5, 1.0, and 2.0 mg, risperidone was found to be effective in controlling the psychosis and behavioral disturbance associated with dementia. The authors recommended using a dosage of 1.0 mg/d because higher dosages resulted in excessive sedation and EPS.¹⁷

Risk of side effects is dose-dependent, especially in the older patient. Risperidone is the only atypical antipsychotic associated with persistent hyperprolactinemia, which may indirectly contribute to increased osteoporosis and atherogenesis.^18,19 Orthostatic hypotension, especially with initial dosages greater than 1.5 mg/d and rapid dose escalation (≥ 25% every 24 to 48 hours), may also limit its use in older patients.

Olanzapine is a thiobenzodiazepine derivative indicated for treatment of psychosis and acute bipolar mania. Olanzapine has a receptor profile that is somewhat analogous with that of clozapine. Its antipsychotic efficacy is equivalent to that of risperidone, but it has a more favorable safety profile. Like risperidone, olanzapine is relatively nonsedating, but it is significantly less likely to cause EPS and orthostatic hypotension, and its use is not associated with persistent hyperprolactinemia.

Based on its vitro muscarinic receptor antagonism profile, some clinicians incorrectly assume that olanzapine is highly anticholinergic. In vivo data and clinical experience have not borne out this contention.^20,21 Weight gain with olanzapine is relatively infrequent in older persons. A rapid-dissolve preparation can be useful in resistant and noncompliant patients. An IM preparation has been approved by the FDA but has not yet been made available by the manufacturer.

Quetiapine is a dibenzothiazepine derivative indicated for treatment of psychotic disorders. Despite limited data on its efficacy in late-life psychosis, clinical experience would suggest that its antipsychotic efficacy would at least equal that of other drugs in this category.

The need for twice-daily dosing and titration to a therapeutic response can sometimes limit the use of quetiapine. Sedation can be a problem at dosages greater than 200 mg/d. Because quetiapine has a relatively lower potential among the antipsychotics to cause EPS, it may be a first-line choice in patients with Parkinson’s disease and Lewy body dementia.

Ziprasidone is a benzothiazolylpiperazine indicated for treatment of psychosis. Experience with its use in older patients is limited. Ziprasidone should be avoided in patients with significant cardiovascular disease because of its potential to cause QT prolongation and cardiac arrhythmias. Although rare, this cardiac side effect may be life-threatening, and clinicians must be exceptionally vigilant when using ziprasidone in older patients. Risk factors for QT prolongation include older age, female sex, pre-existing cardiac disease, hypokalemia, and hypomagnesemia.

Ziprasidone can be somewhat sedating. An IM preparation is under development but has not been approved for use by the FDA

Neuroleptics and other options

Occasionally a typical neuroleptic may be the most appropriate first-line drug for older patients with psychotic symptoms. For example, a mid-potency neuroleptic such as perphenazine at an IM dose of 2 to 4 mg may be considered when severe agitation and aggression pose a substantial safety risk for the patient or caregiver and require rapid control. Haloperidol, despite its widespread use in both acute and long-term settings, should be used with caution because it has great potential for causing EPS and can immobilize an older patient, resulting in further functional decline. Regardless of which typical neuroleptic is used, switch the patient to an atypical antipsychotic as soon as agitation is under control.

Antidepressants Affective psychoses in older patients may require the addition of an antidepressant to the antipsychotic drug. The selective serotonin reuptake inhibitors fluoxetine and sertraline have proven track records for efficacy and safety and should be considered first-line agents.

Other options Electroconvulsive therapy is safe and effective for older patients with psychotic depression or late-life mania. Late-life mania also may respond well to the anticonvulsant divalproex sodium. Avoid anxiolytics in older patients because of the potential of these agents to cause sedation or disinhibition and their associated risk of falls and confusion. Buspirone in higher dosages (40 to 60 mg/d) can sometimes help manage chronic anxiety states.

Related resource

• Sadavoy J, Lazarus LW, Jarvik LF, Grossman GT (eds). Comprehensive review of geriatric psychiatry (2nd ed). Washington, DC: American Psychiatric Press, 1996.

Drug brand names

• Buspirone • Buspar
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Snow reports no affiliation or financial arrangement with any of the companies whose products are mentioned in this article.

Dr. Verma reports that he is on the speakers’ bureau of Eli Lilly and Co. and Abbott Laboratories, serves as a consultant to Eli Lilly and Co., and receives grant support from Eli Lilly and Co. and GlaxoSmithKline.