Psychosis in Neuropsychiatric Disorders

Laura A. Flashman

Thomas W. McAllister

I. Background

A. Definitions

Psychosis is a term that has been defined in a number of ways, and no definition has achieved universal acceptance. Early classifications of psychosis (e.g., Diagnostic and Statistical Manual of Mental Disorders [DSM]-III and ICD-9) focused on the severity of functional impairment rather than specific symptoms; a mental disorder was referred to as “psychotic” if it resulted in impairment that grossly interfered with the capacity to meet the ordinary demands of life.
In its narrowest contemporary definition, the term “psychotic” is restricted to a syndrome characterized by the presence of delusions or prominent hallucinations, with the hallucinations occurring in the absence of insight into their pathologic nature. A slightly less restrictive definition would also include prominent hallucinations that the individual realizes are hallucinatory experiences.
Broader definitions of psychosis include other signs, such as disorganized speech and disorganized, or catatonic behavior. Positive symptoms appear to reflect an excess or distortion of normal functions; in contrast, negative symptoms appear to reflect a diminution or loss of normal functions (e.g., reduced range of affect). Psychosis is usually not diagnosed in the presence of negative symptoms alone.
Disorganized speech typically reflects distortions or exaggerations of language and communication. A person may lose track of
what he or she is saying, moving from one topic to another, circle around a question without ever directly addressing it, or answer questions in a way that is only obliquely related, or even in an unrelated manner.
Grossly disorganized or catatonic behavior can manifest itself in a number of ways, and ranges from silly, childlike behavior to unpredictable agitation. Problems can be seen in goal-directed behavior, or may be manifested by an unusual appearance (e.g., wearing several layers of clothing in the summer) or inappropriate anger (e.g., giving a harangue on a street corner).

B. Classification of psychotic syndromes and disorders

The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (American Psychiatric Association, 1994) identifies a number of disorders that are characterized by having psychotic symptoms as the defining feature (schizophrenia spectrum disorders). It should be noted that there are other disorders that may present with psychotic symptoms, which are not defining features (see Table 7.1).

1. Schizophrenia

Schizophrenia is defined by a combination of psychotic symptoms that significantly impact on major areas of functioning, including work, interpersonal relations, or self-care. Disturbances of emotional, behavioral, cognitive, and perceptual functioning can be observed. Specifically, to meet the DSM-IV criteria for schizophrenia, a person must have two (or more) symptoms (i.e., delusions, hallucinations, disorganized speech or behavior, affective flattening, alogia, or avolition) present for a significant portion of time during a 1-month period (or less if successfully treated), with continuous signs of the disturbance persisting for at least 6 months, which may include
periods of prodromal or residual symptoms. The symptoms must cause clinically significant distress or impairment in social, occupational, self-care, or other important areas of functioning. The median age of onset for the first psychotic episode of schizophrenia is in the early to mid-twenties for men, and in the late twenties for women. The first degree biologic relatives of individuals with schizophrenia have a 10-fold greater risk of developing schizophrenia than the general population, but both genetic and environmental factors have been shown to play a role in the development of schizophrenia.

TABLE 7.1 Classification of Psychotic Syndromes and Disorders

Psychosis as defining feature (“primary psychosis”)

Schizophrenia
Schizophreniform disorder
Schizoaffective disorder
Delusional disorder
Brief psychotic disorder
Shared psychotic disorder
Psychotic disorder due to a general medical condition
Substance-induced psychotic disorder
Psychotic disorder, not otherwise specified

Presence of psychotic symptoms, not defining features

Dementia of the Alzheimer type
Substance-induced delirium
Major depressive episode, with psychotic features
Manic episode, with psychotic features
Mixed episode, with psychotic features

2. Schizophreniform disorder

When the duration of the illness has been at least 1 month, but<6 months, a diagnosis of schizophreniform disorder is given. The essential features of this disorder are identical to those of schizophrenia, with two exceptions: (a) The total duration of the illness (including prodromal, active, and residual phases), as noted in the preceding text; and (b) impaired social and/or occupational functioning during some part of the illness is not required, although most individuals do experience dysfunction in various areas of daily functioning (e.g., work or school, interpersonal relationships, or self-care). Approximately two thirds of individuals with an initial diagnosis of schizophreniform disorder will progress to the diagnoses of schizophrenia or schizoaffective disorder.

3. Schizoaffective disorder

The essential feature of schizoaffective disorder is an uninterrupted period of illness during which there are concurrent mood and psychotic symptoms so that the full criteria are met for both a major depressive, manic, or mixed episode (see Chapter 5), as well as the symptoms of schizophrenia (i.e., delusions, hallucinations, disorganized speech or behavior, affective flattening, alogia, or avolition). In addition, during the same period of illness, there must be delusions or hallucinations for at least 2 weeks in the absence of prominent mood symptoms. Disturbances of emotional, behavioral, cognitive, and perceptual functioning are observed. Detailed information is lacking, but schizoaffective disorder appears to be less prevalent than schizophrenia.

4. Psychotic disorder not otherwise specified

This diagnosis is used when psychotic symptomatology (i.e., delusions, hallucinations, disorganized speech, grossly disorganized, or catatonic behavior) is present in the context of inadequate information to make a specific diagnosis, or about which there is contradictory information. It can also be used to characterize disorders with psychotic symptoms that do not meet the criteria for any specific psychotic disorder.

C. Epidemiology

Psychotic symptoms and syndromes are reported to be much more common in patients with certain neurologic disorders than in control or reference populations (see Table 7.2). The precise prevalence rates are difficult to establish given wide methodologic variation in the published reports. The highest rates of psychosis have been reported in patients with Alzheimer disease (AD) (∼50%),
dementia with Lewy bodies (DLB) (up to 80%), Parkinson disease (PD)(∼20% to 25%), and epilepsy (2.8% to 27%). Nevertheless, even in those disorders in which it occurs with lower frequency, psychosis poses a significant complication, and results in significant distress to both individuals and their caregivers, decreases quality of life, and increases likelihood of nursing home placement.

TABLE 7.2 Prevalence of Psychosis in Patients with Neurologic Disease

Alzheimer disease	∼10%–70%; 50% estimates common
Lewy body dementia	Up to 80% have complex visual hallucinations
Parkinson disease	∼20%–25%
Epilepsy	0%–27%; 2.8%–7.1% in larger, more rigorous studies
Traumatic brain injury	∼0.7%–9.8%
Intellectual disability	∼2%–8%; higher in selective ID syndromes
Huntington disease	∼0.5%–8%
Multiple sclerosis	0%–5%
Poststroke	Rare
ID, intellectual disability.

D. Prognosis

A much smaller literature exists on the course and prognosis of psychosis associated with a neuropsychiatric illness. These limited data suggest that psychosis in the context of a neuropsychiatric illness may persist for months and even years after onset and its presence may increase both the morbidity and mortality of the illness (see discussion of specific illness in subsequent text).

II. Neurobiology and Pathophysiology of Psychosis

A. Schizophrenia spectrum disorders

The pathophysiology of schizophrenia spectrum disorders is not fully understood. Several regions in the brain appear to play important roles in the genesis and phenomenology of schizophrenia. The temporal lobes, particularly the left temporal lobe, including the hippocampal formation, appear to play a role in auditory hallucinations and some delusions. Abnormalities of right hemispheric function, particularly in parietal and frontal cortices, have also been associated with delusions of misidentification. Delusions of passivity and control have been linked to abnormalities of left temporal cortex. Several lines of evidence from neuropathologic studies and functional imaging studies suggest that dorsolateral prefrontal cortex is disordered in individuals with schizophrenia and probably accounts for observed cognitive deficits associated with the illness (e.g., working memory deficits) as well as problems in motivated behavior (e.g., apathy). Psychosis may be the result of genetically determined defects in neurotransmitter function, which may occur de novo or in response to psychosocial stress (the stress-diathesis model).

1. Psychosis in patients with a neurologic illness

The pathophysiology of psychosis in patients with neurologic illness is not known, but is likely to be heterogeneous. In terms of DSM-IV diagnoses, psychosis in the context of these neurologic disorders is referred to as “Psychosis due to a General Medical Condition,” with the specific disorder identified as the medical condition. Psychosis in patients with a neurologic illness may reflect some combination of a recurrence of a preexisting psychiatric disorder, a result of other neurologic or general medical problems, a direct effect of the neurologic illness on particular brain systems (endogenous factor), or be related to the therapeutic interventions being used to treat the primary disorder (exogenous factor).

Studies in patients with neuropsychiatric disease suggest a relation between psychosis and lesions of particular brain regions including frontal lobe dysfunction (cerebrovascular disease, AD, traumatic brain injury [TBI]), the temporal lobes including the hippocampus (TBI, epilepsy), and the basal ganglia and thalamus (TBI). Abnormalities in neurotransmitter and other receptors have also been implicated in some of these disorders (AD, PD), and other brain and genetic factors, such as density of neurofibrillary tangles (AD, Lewy body dementia [LBD]), demyelination (multiple sclerosis [MS]) and CAG repeat length (Huntington disease[HD]) have also been implicated (see subsequent text).

III. Management

A. Principles of management

The literature on the treatment of psychosis associated with neurologic disorders is quite sparse and does not rise to the level that would permit illness-specific practice guidelines. There are no medications with U.S. Food Drug Administration (FDA) indications for the treatment of psychosis associated with any given neurologic disorder. On the other hand, numerous case reports, small case series, and our clinical experience suggest that these individuals will respond to treatment approaches similar to those that have evolved for the treatment of schizophrenia spectrum disorders. Therefore, in general, the management of psychosis in patients with neurologic illness (regardless of whether the psychosis is considered to be “secondary” to the neurologic illness) should follow the Practice Guidelines for the Treatment of Patients with Schizophrenia, Second Edition by the American Psychiatric Association.

1. Perform a diagnostic evaluation

The diagnosis of a psychosis in patients with neurologic illness can be challenging. Some controversy exists about the most appropriate method for diagnosing psychosis in patients with neurologic or medical conditions, because some of the signs or symptoms (e.g., confusion, illusions) may result from the medical or neurologic illness. Further, medications used to treat these disorders may themselves result in psychotic symptoms. An additional diagnostic challenge relates to the assessment of symptoms that require
verbal expression (e.g., hallucinations, delusions, etc.) in patients who cannot speak (e.g., due to an aphasia) or clearly express themselves (e.g., due to an intellectual disability [ID] with limited vocabulary). In such cases, it may be necessary to give greater weight to clearly manifest signs of the psychotic disorder such as consistent misinterpretation of events in the environment in a paranoid fashion or apparent repetitive responses to internal stimuli.

Psychosis in individuals with neurologic disorders can be seen in several different settings. The first can be attributed to the neurologic disorder itself and is thought to occur when the illness involves or spreads to the brain regions critical in the genesis of psychotic symptoms that have already been described. The second context is psychosis occurring as part of a delirium or metabolic encephalopathy. This occurrence is typically seen in neurologic disorders occurring in the elderly or those that have common medical comorbidities. Iatrogenic causes, often related to medications used to treat the underlying illness, is another common cause of delirium. A third context is the development of a mood disorder with psychotic features. Most disorders of the central nervous system (CNS) have markedly increased rates of mood disorders (see Chapter 5). Both depression and mania can present with psychotic features. The fourth context is psychotic symptoms precipitated by substance use or abuse. Psychotic symptoms can also be seen in individuals with seizure disorders. Most commonly this occurs in the context of complex partial seizures, particularly when the seizure focus is in the temporal or frontal lobes. Psychotic symptoms can be seen ictally, postictally, or interictally (usually after many years of having a seizure disorder).

The diagnosis of new psychotic symptoms in the individual with neurologic disease should involve determining which of the “causes” mentioned in the preceding text are responsible. A neurologic examination and perhaps other neurodiagnostic studies like (electroencephalography [EEG], repeat neuroimaging) should be considered to ascertain whether the underlying neurologic disorder has progressed. A careful cognitive examination and history should be taken to determine whether the individual is delirious. If there is any suggestion of a delirium, screening laboratory studies (complete blood count [CBC], serum electrolytes, blood urea nitrogen [BUN], Cre, Ca++) should be done to determine the cause of the delirium. A careful history from the individual and reliable informants should be taken looking for indicators of a mood disorder. A urine toxicology screen should be done if there is any possibility of substance use. Psychotic symptoms of paroxysmal onset with brief duration, especially in the context of a
known or suspected seizure disorder should prompt strong consideration of an EEG.

The judgment that the psychosis is secondary to the neurologic illness requires confirmation of a neurologic illness, evidence that the psychosis is a “direct physiological consequence” of that illness, and evidence that the psychosis is not better accounted for by another mental disorder.Determining whether the psychotic symptoms are “a direct physiological consequence” of the neurologic illness may be very challenging indeed, as there are no clear rules for establishing such an association. A potential relation is suggested by a temporal association between the neurologic illness’s onset, exacerbation, or remission and that of the psychotic disorder (e.g., the psychosis begins shortly after the stroke); atypical features of a psychotic disorder; or a well-established relation between the psychotic disorder and the neurologic illness (e.g., as in the conditions listed in Table 7.2). However, certain disorders such as epilepsy and TBI can have lengthy latencies between onset of the disease and emergence of psychotic symptoms (often several years for both disorders). The absence of any premorbid indicators of psychotic symptoms or related prodrome, as well as the absence of family history of psychotic disorders, are also supportive evidence of an etiologic connection between the neurologic disorder and the psychosis.

TABLE 7.3 Selected Medications for Treatment of Psychotic Symptoms

Medication	Starting Dose per Day	Dosing Range per Day
Typical antipsychotics
Haloperidol	0.25–0.5 mg	0.25–4 mg
Atypical antipsychotics
Risperidone	0.25 mg	0.25–4 mg
Aripiprazole	5 mg	5–15 mg
Clozapine	12.5 mg	12.5–300 mg
Quetiapine	12.5–25 mg	12.5–300 mg

2. Implement a biopsychosocial treatment plan

We discuss in the subsequent text specific recommendations for treatment of psychosis in patients with some of the more common neurologic illnesses.

Development of a therapeutic alliance and promotion of treatment adherence. It is important to develop an alliance in a patient with psychosis. Many individuals, especially those with neurologic disorders, are resistant to being labeled as having a psychiatric disorder, especially a psychosis. This resistance can take the form of both a “psychological”
denial (not wanting to be labeled as “crazy”) as well as a deficit in self-monitoring and awareness of illness behavior. The latter shares many features with lack of awareness of neurologic symptoms, often referred to as anosognosia.
Patient and family education and therapies. Helping patients and families recognize early symptoms of relapse to prevent full-blown illness exacerbations is critical. Further, education to the family and caregivers about the nature of the illness and possible psychiatric symptoms, as well as coping strategies to diminish relapses and improve quality of life of patients is an important component of successful treatment.
Treat comorbid conditions. These comorbidities might include major depression, substance use disorders, or even physical discomfort or pain. Impaired processing of perceptual information is often a prominent aspect of psychotic disorders. Physical symptoms such as pain or discomfort may be either incorrectly perceived or misinterpreted by the affected individual. Somatic symptoms may occur in patients with psychosis and worsen their psychotic states, but may only be recognized later as physical problems. Patients with psychosis may be unable to comprehend or describe their physical symptoms adequately. Physical disorders of patients with psychosis may be overlooked if clinicians are not vigilant and thorough in assessing the patients’ complaints, especially if such complaints sound delusional or bizarre. Problems with speech and language function are an important component of many brain disorders and can limit the individual’s capacity to accurately report or describe physical symptoms that would ordinarily tip-off the alert clinician to the presence of significant medical disorders.
Attend to patient’s social circumstances and functioning. An important goal is to work with team members, the individual, and the family to ensure that services are coordinated and that referrals for additional services are made when appropriate. This component is also often overlooked. Individuals with neuropsychiatric disorders frequently do not fit easily into standard systems of medical care (they are often perceived as “bad patients” or “acting out” in some willful fashion), nor community mental health systems or related agencies (behaviors often overattributed to the “medical issues” or “medical involvement”).
Integrate treatment from multiple clinicians. This issue is important in patients with a neurologic illness, who are likely being followed by a primary care physician and a neurologist in addition to other specialists.
Document treatment. Documentation of treatment is also very important, because patients may have different practitioners over the course of their illness. Information about successful and unsuccessful therapies is very helpful to
minimize multiple trials of medications, and detail clearly the interventions that have and have not worked in the past.
Finally, it is important to recognize that for all individuals with neuropsychiatric illness and psychotic symptoms, psychiatric hospitalization may be needed in the acute stages.

B. Psychosis in individuals with particular neurologic disorders

1. Psychosis in Alzheimer disease

a. Clinical background

The reported prevalence of psychotic symptoms in patients with AD varies, but has been reported to be as low as 10% to 15% and as high as 50% to 70%. The incidence of new onset psychosis in AD has been reported to be approximately 30% over the course of 2 years.
Several identified risk factors have been associated with psychosis in AD. These include gender, education, and race. Women have been reported to have a higher risk of developing psychosis within 2 years than men. Education has been associated with psychosis in mild or moderate stages of the dementia, whereas race has been associated with psychosis in moderate or severe stages. Psychotic symptoms, such as delusions and hallucinations may occur with increased frequency in individuals with certain genotypes. Candidate genes and related polymorphic alleles that have been identified as increasing the risk of psychotic symptoms include the long allele of an insertion or deletion polymorphism in the promoter region of the serotonin transporter (5-HTTPR), the 102C allele in the serotonin 2A receptor, and selected polymorphisms in the dopamine receptor genes DRD1 (B2 allele) and DRD3 (l allele). In addition linkage signals on chromosome 2p (near marker D2S1356), chromosome 6 (near marker D6S1021) and chromosome 21 (near D21S1440) have also been identified. The apolipoprotein (APOE) and α₁-antichymotrypsin (ACT) genotypes do not appear to contribute to the risk of development of psychotic symptoms in AD. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings.
The phenomenology of psychosis in patients with AD is associated with more severe cognitive deficits and a more rapidly deteriorating course. Two subtypes of psychosis in AD have been proposed: One involving misidentification and hallucinations, and the other involving persecutory delusions. Agitation has been associated with aggression and psychosis in mild or moderate stages, and psychosis was associated with aggression in moderate or severe stages of AD. Further, a constellation of psychiatric symptoms (e.g.,
anxiety, wandering, irritability, inappropriate behavior, uncooperativeness, emotional lability) has been associated with agitation, aggression, and psychosis, and reportedly varies according to the severity of the dementia, suggesting a progressive deterioration of frontal-temporal limbic structures.
The longitudinal course of psychosis in AD is not fully known, although it has been noted that agitation, aggression, and psychosis are more frequently seen in the later stages of the disease.

b. Pathogenesis

The pathophysiology of psychosis in patients with AD is not completely understood, but an association between psychosis and neurofibrillary tangle density has been inconsistently reported.
Increased frontal lobe dysfunction (on the basis of neurobehavioral, cognitive, and single photon emission computed tomography [SPECT] measures) has been reported in patients with AD and psychosis. Quantitative EEG results indicate that patients with psychosis have greater overall absolute and relative delta power, and a concomitant decrease in relative α-power, with no regional predominance of slowing compared with those patients with AD and no psychosis.
Functional neuroimaging data suggests increased orbitofrontal and midtemporal cholinergic M2 receptors with psychosis and hallucinations. Paranoid delusions have been associated with left dorsolateral prefrontal and left medial temporal decreases in activation on positron emission tomography.
Patients with AD and psychosis have also been found to demonstrate significant elevations of glycerophospho-ethanolamine and significant reductions of N-acetyl-L-aspartate, suggesting that excess impairment of neocortical, neuronal, and synaptic integrity may provide the structural substrate underlying psychosis in AD.

c. Diagnosis

The diagnosis is clinical and is based upon the presence of psychotic symptoms. However, if the dementing process impairs speech and language function, the individual may not be able to articulate or describe the symptoms and they may have to be inferred from the individual’s behavior, as described under general principles. It is critical to determine what the underlying cause of the psychosis is. As with other neurologic disorders, psychosis in dementing disorders can be seen in several different settings including (1) as part of a delirium or metabolic encephalopathy, (2) as a component of a mood disorder, (3) as part of a seizure disorder or (4) related to substance use or abuse (less common in this context).
Given that dementing disorders occur most commonly in the elderly with associated medical disorders, iatrogenic causes, often related to medications used to treat the underlying illness, is a common cause of delirium with associated psychotic symptoms.

The evaluation of new psychotic symptoms in the individual with dementia should involve determining which of the “causes” mentioned in the preceding text are responsible. A careful cognitive examination and history should be taken to determine whether the individual is delirious. If there is any suggestion of delirium, screening laboratory studies (CBC, serum electrolytes, BUN, Cre, Ca++, urinalysis and culture) should be done to determine the cause. A careful history from the individual and reliable informants should be taken looking for indicators of a mood disorder. A urine toxicology screen should be done if there is any possibility of substance use. Psychotic symptoms of paroxysmal onset with brief duration, especially in the context of a known or suspected seizure disorder should prompt strong consideration of an EEG.

d. Treatment

Optimize the physical health of the patient and ensure that all underlying general medical disorders have been optimally treated, including pain management.
Optimize the patient’s environment and lifestyle, including the provision of a safe situation that minimizes the person’s acting on delusions or hallucinations in a dangerous or violent manner. This type of behavior can put patients at risk for being overmedicated or restrained. Those living at home or in assisted living facilities are at increased risk for institutionalization.
In addition to environmental modification, behavioral management techniques could include optimization of socialization and functional status, and education and support of caregivers. Caregivers of patients with psychosis and AD can experience considerable adversity, including increased physical demands involved in constant supervision of the patient, the emotional stress of caring for a loved one who is experiencing these symptoms, physical illness, and depression.
Medication approaches—The use of medications to treat psychosis in dementia varies according to what is “causing” the psychosis.
- Delirium. Determine cause; treat accordingly (e.g., correct electrolyte imbalances, discontinue causative medications etc.). Use low-dose antipsychotic agents (see subsequent text).
- Mood disorder. Treat depression with antidepressants or mania with anticycling agents (see Chapter 5). If psychosis is endangering health and
  well-being of the patient, family or caregiver, add low-dose antipsychotic agents (see subsequent text).
- Seizure disorder. In this context the usual seizure disorder is a complex partial seizure. Therefore, management of the seizure disorder becomes the primary concern. Management suggestions are beyond the scope of this chapter. The paramount treatment objective is control of the seizure frequency. If psychosis is endangering health and well-being of the patient, family or caregiver, add low-dose antipsychotic agents (see subsequent text).
- Substance use or abuse. In this context, the treatment objective becomes the identification and removal of the offending drug of abuse. If psychosis is endangering health and well-being of the patient, family or caregiver, add low-dose antipsychotic agents (see subsequent text).
- Use of cholinesterase inhibitors. When the psychosis is considered to be caused by the underlying dementing disorder, or when caused by one of the conditions mentioned in the preceding text in a circumstance in which the symptoms are endangering the health and well-being of the patient, family or caregiver, the use of medications is warranted. There are no FDA-approved medications for the treatment of psychosis in patients with AD. There is evidence, however, from controlled trials suggesting that neuropsychiatric symptoms, including psychotic symptoms can be improved with the use of cholinesterase inhibitors (see Chapter 4). If the symptoms are subacute and nonthreatening, these agents should be tried first. We suggest starting with donepezil 5 mg daily. The dose may be raised to 10 mg daily if the lower dose is ineffective but well tolerated for at least 4 weeks. Treatment-emergent side effects may include gastrointestinal symptoms, muscle cramping, frequent urination, and sleep disturbance (i.e., vivid dreams or nightmares). These side effects may respond to dose reduction and/or a slower dose titration schedule. Baseline and periodic liver function tests should be done. If there is no response to this regimen or side effects preclude its use, then we suggest rivastigmine 3 to 9 mg per day in divided doses.
- Use of antipsychotic medication. If the symptoms are endangering the health and well-being of the
  patient, family or caregiver the use of antipsychotic medication is warranted. There are important issues to consider with both the typical and atypical antipsychotics. The typical antipsychotics tend to cause more extrapyramidal effects and carry a higher risk of tardive dyskinesia, probably related to the degree of D2 receptor blockade. The associated psychomotor slowing, tremor, motor rigidity, cognitive slowing, and abulia associated with these medicines may exacerbate some challenging behaviors already present because of the stroke.
  
  The atypical antipsychotics generally have less D2 receptor blockade and more 5HT1 antagonism relative to the typical antipsychotics. They are felt to carry less risk of extrapyramidal symptoms (EPS) and tardive dyskinesia. On the other hand, there is significant risk of weight gain, diabetes, and metabolic syndrome. There have been several published reports of increased risk of stroke and related cerebrovascular events in the elderly associated with these medicines. This risk has resulted in a recent, highly publicized “black box” warning and a concern about their use in individuals already predisposed to stroke. However, two recent studies have failed to find an increased risk of stroke in the elderly associated with the use of atypical antipsychotics, and raise the possibility that the earlier findings might be attributable to increased percentages of individuals with vascular dementia (and therefore at increased risk for cerebrovascular disease) in the risperidone group. Furthermore, some studies suggest that the risk of cerebrovascular events may be increased for all individuals on antipsychotic medications, regardless of the typical or atypical designation.
  
  The case report and small case series literature is flawed but does suggest that both classes of agents can be effective. However, atypical antipsychotics have been examined in large randomized placebo-controlled trials and found effective (e.g., low-dose risperidone [0.95 to 2 mg per day] and olanzapine [2.5 mg starting dose, with a significant decrease in psychosis at 5 to 7.5 mg per day]). We suggest the following although the level of evidence to support it is weak.

Assuming little risk of metabolic syndrome or diabetes in these individuals, we will start with an atypical agent. We use risperidone, 0.25 mg or 0.5 mg per day and titrate slowly upward, rarely going >4 mg per day. If weight gain
or other signs of metabolic syndrome emerge we cross taper to aripiprazole, 5 mg per day and titrate slowly to 15 mg per day as tolerated. If psychotic symptoms do not abate after 1 month we then consider another atypical, or use a typical agent such as haloperidol starting at 0.5 mg per day, titrating upward as needed and tolerated to 2 to 4 mg per day. If an effective treatment is found, we continue it for 6 to 12 months as tolerated and then attempt to slowly (2 months) taper off the medications.

References

1. Assal F, Cummings JL. Neuropsychiatric symptoms in the dementias. Curr Opin Neurol. 2002;15:445–450.

2. Bacanu SA, Devlin B, Chowdari KV, et al. Linkage analysis of Alzheimer disease with psychosis. Neurology. 2002;59:118–120.

3. Reeves RR, Torres RA. Orally disintegrating olanzapine for the treatment of psychotic and behavioral disturbances associated with dementia. South Med J. 2003;96:699–701.

4. Sultzer DL. Psychosis and antipsychotic medications in Alzheimer’s disease: Clinical management and research perspectives. Dement Geriatr Cogn Disord. 2004;17:78–90.

2. Other dementing disorders—overview

Many of the principles and specific treatments described in the preceding text are applicable to other dementing disorders including vascular dementia and the reader is referred to the preceding section and to Chapter 4. Psychotic symptoms in two other common dementing disorders—DLB and PD—are worth commenting specifically upon.

3. Dementia with Lewy bodies

a. Clinical background

Prevalence and occurrence. DLB is in some series second only to AD as the most prevalent cause of dementia.
Phenomenology. Individuals with DLB may present fairly early in the course of illness with psychotic symptoms, particularly visual hallucinations. Up to 80% of individuals with DLB will have complex visual hallucinations, often associated with a variety of illusions and misidentification syndromes.
Course and prognosis. The Consortium on Dementia with Lewy Bodies describe DLB as a progressive and often rapidly disabling dementia in which attentional impairment, executive dysfunction, and visuospatial difficulties occur early and prominently. Fluctuating cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are also core elements of DLB. The average age of onset is in the seventh decade, and the average life span after diagnosis is 6 to 7 years. There are no known disease-altering treatments.

b. Pathogenesis

DLB is a dementing disorder characterized pathologically by the presence of clumps of α-synuclein protein, identified microscopically as Lewy bodies. The abnormal clusters of protein in turn trigger an inflammatory response, impairment of the ubiquitin proteasome catabolic system, and triggering of the apoptotic cascade resulting in cell death.
In addition to the widespread distribution of Lewy bodies, there are characteristic deficits in certain neurotransmitter systems including loss of cholinergic tone because of damage to cholinergic neurons in the basal forebrain nuclei, and indications of dysregulation of catecholaminergic and indolaminergic systems.
A significant inverse correlation between persistent visual hallucinations and tangles has been reported (i.e., visual hallucinations were associated with the presence of less severe tangle pathology), although there was no significant association between tangle pathology and persistent delusions. Severity of illness has also been significantly correlated with the presence of persistent visual hallucinations and persistent delusions. Baseline psychotic features are reported to be significantly more frequent in DLB than in AD.

c. Diagnosis

This disorder is often mistaken for PD because of overlapping clinical and neuropathologic features between the two disorders. The diagnosis of psychosis in DLB is clinical and is based on the presence of symptoms that meet the criteria for a psychotic disorder. However, visual hallucinations are relatively more common in this context than other psychotic syndromes. It is critical to determine what the underlying cause of the psychosis is; in addition to being a symptom of the disorder itself, psychotic symptoms can be seen (1) as part of a delirium or metabolic encephalopathy, or (2) as a component of a mood disorder. Other causes are less likely in this context. Given that DLB occurs most commonly in the elderly with associated medical disorders, iatrogenic causes (often related to medications used to treat the underlying illness) are a common cause of delirium with associated psychotic symptoms.

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