Psychosis and Depression in the Elderly 0193-953X/88 $0.00+ .

20

Neuroleptics and Alternative

Treatments
Management of Behavioral Symptoms and
Psychosis in Alzheimer's Disease
and Related Conditions

Robin E. Wragg, M .D .* and Dilip V. ]este, M .D .f

Dementia occurs in at least 5 per cent of the population age 65 or

over. 66 Estimates suggest 20 per cent of the population may be affected by
age 80. Alzheimer's disease (AD) accounts for approximately 60 per cent of
all cases of dementia in patients greater than age 65 years. Behavioral and
psychotic symptoms are frequent concomitants of dementia, including Alz-
heimer's disease. 68 They were integral features of Alzheimer's initial case
report3 and have been recognized as "other clinical features consistent with
a diagnosis of probable AD" in the NINCDS-ADRDA Task Force report. 53
When they occur, behavioral and psychotic symptoms are distressing to the
patient and primary caregiver as well as difficult to manage for the medical
provider. However, these symptoms have received relatively little system-
atic examination until recently. A relationship to cognitive performance or
affective states is presumed but has not been firmly established.
Previous studies in the demented elderly report that control of behav-
ioral and psychotic symptoms is critical. In a naturalistic study of problem
behaviors and symptoms as reported by primary caregivers, Rabins et al. 64
found specific psychotic symptoms (hallucinations, delusions) in approxi-

*Assistant C linical Professor; Fellow, Research Program in Geropsychiatry and Neuropsychia-

try, Department of Psychiatry, San Diego Veterans Administration Medical Center, and
University of California, San Diego, La Jolla, California
tProfessor of Psychiatry; Director, Program in Geropsychiatry and Neuropsychiatry, Division
of Geropsychiatry and Neuropsychiatry; Department of Psychiatry, San Diego Veterans
Administration Medical Center, and University of California, San Diego, La Jolla, Cali-
fornia

This work was supported in part by the Veterans Administration (Research training award
to REW and Geropsychiatry Program headed by DVJ)
Psychiatric Clinics of North America-Vol. 11, No. 1, March 1988 195
196 ROBIN E. WRAGG AND DILIP V. }ESTE

mately 50 per cent of patients and disruptive behaviors (physical violence,

hiding things, wandering, and demanding and critical behavior) in up to 70
per cent. Caregivers cited these behaviors as constituting serious problems
that materially affected the quality of life for both patient and caregiver.
Although these data may be subject to reporting bias by distressed caregiv-
ers, the frequencies cited indicate a problem of considerable magnitude.
Several studies 15• 24 • 78 suggest that even modest improvement in trouble-
some behaviors may result in substantial improvements in function,
whereas their unmodified continuation may be a primary determining rea-
son for institutionalization. 24
Unfortunately, whereas the need for effective treatment strategies is
clear, there is no definitive intervention to meet this need. The underlying
neurobiology of behavioral and psychotic symptoms in the dementias is
poorly understood as is the interaction between such factors and contribut-
ing social and environmental variables. Because of this relative dearth of
understanding, treatment may occur in the absence of a clear therapeutic
rationale. Neuroleptics are the most widely used and studied of currently
available treatments. Because the positive effects of neuroleptic treatment
may be quite striking in some instances, their empiric use is sometimes
tempting and often pragmatic. However, it is not entirely clear that the
benefits of neuroleptic treatment outweigh the risks. These circumstances
are even more compelling for potential alternatives to neuroleptic treat-
ment, pharmacologic or psychotherapeutic.

BEHAVIORAL AND PSYCHOTIC SYMPTOMS

Behavioral Symptoms: "Agitation"
Most disruptive behavioral symptoms in the demented elderly would
be subsumed by the term agitation. Cohen-Mansfield and Billig19 recently
reviewed the problem of defining, measuring, and modifying agitated be-
havior in the elderly. They suggested that agitation might be categorized
as "inappropriate verbal, vocal, or motor activity that is not explained by
needs or confusion per: se." Such activity may be inherently inappropriate
because it is abusive or aggressive to self or others, or it may be otherwise
appropriate behavior that is inappropriately repetitious or inappropriate to
the specific social context. Individual agitated behaviors appear to be highly
correlated; nonaggressive, repetitious behaviors occur most commonly. 18
Accurate prevalence rates are difficult to ascertain; however, available data
suggest approximately 70 to 80 per cent of patients manifest this behavior
in some form. 18 • 64
Other specific disruptive behaviors occur in low frequency, such as
sexually inappropriate behavior, 64 or can be attributed directly to needs or
confusion such as incontinence and inability to maintain adequate personal
hygiene and grooming.
Psychotic Symptoms
Psychotic symptoms in the demented elderly have presented similar
problems of definition, measurement, and intervention. In demented pa-
NEUROLEPTICS AND ALTERNATIVE TREATMENTS 197
tients, psychotic symptoms usually refer to disordered perception or
thought content. The presence of global cognitive impairment precludes in-
clusion of disordered thought process in most cases. However, cognitive
dysfunction also complicates ascertainment of specific expression of delu-
sions or hallucinations; thus, these symptoms are often inferred from dis-
ruptive behaviors .
Although there is some agreement on the clinical phenomenology of
psychotic symptoms in dementia, the incidence, prevalence, and natural
history of these symptoms have not been clearly established. Paranoid de-
lusions, typically of the simple persecutory type, are the most commonly
described individual symptom. The preponderance of published studies
cite prevalence of between 15 and 35 per cent (averaging around 30 per
cent) although some studies note frequencies as extreme as 10 per cent
or 75 per cent. 11 · 22· 23 · 26 · 41 · 44 · 47 · 51 · 74 · 80· 95 Hallucinations occur less fre-
quently, io, 23 · 26· 44 with visual hallucinations (averaging 19 per cent) slightly
more common than auditory hallucinations (averaging 16 per cent). Some
form of psychotic symptom affects nearly 40 per cent of all demented pa-
tients at some point in their course, although one recent study suggests this
may actually reach as high as 60 per cent. 39 Most evidence suggests that
the overall frequency of psychotic symptoms is similar in AD and other de-
mentias though the frequencies of specific symptoms may vary. Paranoid
delusions are typically somewhat more common in AD, whereas hallucina-
tions may be more common in other dementias (Table 1).
Features Associated with Behavioral and Psychotic Symptoms
Various associated features of the dementias have been connected with
the presentation of psychotic symptoms in demented patients. Mayeux and
coworkers 51 suggest an association of psychotic symptoms with neurologic
manifestations, specifically extrapyramidal signs; psychotic symptoms occur
two to three times as frequently in that setting. Similarly, both visual and
auditory sensory impairment 10 are more common among demented patients
with psychotic symptoms. However, the form of sensory impairment does
not appear to be associated with the type of psychotic symptoms observed.
Several studies address the association of degree of cognitive impair-
ment and psychotic symptoms. The majority 9• 23 • 26 · 74 suggest that delusions
are more likely to occur with higher cognitive scores, offering some support
for the hypothesis that some degree of cognitive integrity may be necessary
to generate and maintain delusions. 22 In contrast, other studies 17· 79 · 80 sug-
gest that psychotic symptoms are more common late in the course of de-
mentia, presumably when cognitive function is further diminished. All
relevant studies have been cross-sectional with respect to this particular
question. Consequently, while it seems clear that an association should ex-
ist, the exact nature of the association remains obscure.
Though rudimentary, these observations constitute a preliminary
guide to identifying patients at risk for behavioral and psychotic symptoms
and delineating target symptoms for potential treatment. Although the Re-
port of the APA Task Force on Late Neurological Effects of Antipsychotic
Drugs5 identifies the control of agitation or psychosis in organic mental syn-
dromes as an appropriate indication for short-term use of neuroleptics,
 ......
~
r;,,

Table 1. Selected Studies of Behavioral and Psychotic Symptoms in Dementia

SAMPLE SIZE PSYCHOTIC SYMPTOMS

STUDY AD OD PATIENT SOURCE Paranoid Delusions Hallucinations

Rothschild 74 31 29 State hospital 23% ,.

Goodman 26 23 State hospital " common AH 13% I VH 22%
Ziegler95 40 29 Psychiatric hospital 15%
Sim et al. 80 35 21 General hospital psychiatric ward 24%
Birkett11 10 14 State hospital 10%
Liston 47 46 4 General hospital psychiatric ward 22% :i:i
Berrios8 74 26 Geropsychiatry referrals AD: 28% I OD: 27% 0
Cummings22
Leuchter & Spar44
4
14 15
Neurobehavioral referrals
Geriatric psychiatry unit
15%
73% AH 33% I VH 27%
z°"
!:Tl
Jorgensen41 9 10 Community psychiatric clinic 53%
Cummings et al. 23 30 15 Neurobehavioral referrals AD: 30% I MID: 40% AD: AH 3% I VH 0% ~
MID: AH 13% I VH 20% ~
J este et al. 39 25 14 Dementia research center AD: 60% I OD: 14% 20% overall 0
0
>
z
AD: Alzheimer's disease, OD: Other dementias, MID: Multi-infarct dementia, AH: Auditory hallucinations, VH: Visual hallucinations ti
0
Fi
:a
:<
._
trJ
...,
CJ)

trJ
NEUROLEPTICS AND ALTERNATIVE TREATMENTS 199
otherwise unmanageable behavior symptoms in dementia are considered
only a secondary indication for continuous long-term (greater than 6-
months) use . We will explore the evidence for neuroleptic efficacy in de-
mentia, indications and contraindications for this use, and possible adjuncts
and alternatives to neuroleptic treatment in the remainder of this article .

INDICATIONS FOR NEUROLEPTICS IN TREATING BEHAVIORAL

AND PSYCHOTIC SYMPTOMS
Pharmacology
A detailed consideration of the pharmacology of neuroleptic agents is
beyond the scope of this article; readers may wish to refer to a recent com-
prehensive review. 13 The pharmacokinetic effects of aging and potential
drug-drug interactions with neuroleptics are presented in the article by
Rizos et al. in this volume.
Dementia
Neuroleptics are widely advocated for the control of psychotic symp-
toms in the demented elderly, but are more broadly used for behavior
management. A multicenter study of psychotropic drug use in elderly psy-
chiatric patients (organic brain syndromes, schizophrenia, and other mental
disorders) reported neuroleptics to be the most frequently prescribed drugs
regardless of diagnostic category. 63 In a recent population-based study from
London, Gilleard and coworkers 25 demonstrated that 13 per cent of all el-
derly patients in hospitals, nursing homes, or other institutions had re-
ceived neuroleptics in the previous 24 hours. Of interest, institutional,
rather than patient, factors appeared to play a significant role in determin-
ing who received neuroleptics (Table 2).
The efficacy of neuroleptic use in patients with AD and other de-
mented elderly has been extensively studied. Many studies 1• 4 · 12· 14 · 16 · 20 ·
21, 21, 30, 31, 34, 43, 59 , 65, 73 , 76 · 83 · 85 · 89 have been uncontrolled or limited by numer-

ous other methodologic problems. Major problem areas are imprecise case
definition, inconsistent subject selection and source, and poorly specified
treatment protocols (including failure to use randomization, controls, and
double-blind assessment; to evaluate specific target symptoms, their sever-
ity, and the magnitude of improvement as well as global, nonspecific im-
provement; and to continue treatment for a consistent and adequate
duration).
In general, these reports produced equivocal results although there
were some consistent observations. All neuroleptics studied have been
therapeutically useful with no clear therapeutic advantage or difference
noted among various agents . As a class, neuroleptics appear to be superior
to other classes of psychotropic drugs in treating behavioral disturbance
with or without actual psychotic symptoms; however, systematic, well-
controlled, comparative treatment trials addressing this issue are
rare. 32• 66 • 75 Although a positive therapeutic response to neuroleptics has
been noted in the majority of patients, it has typically been modest and
often no greater than responses to placebo. In some instances, neuroleptic
treatment contributed to deterioration in function, 66 an observation consis-
 l-Q
0
0

Table 2. Evaluations of Efficacy of Neuroleptic Drugs for Behavioral and Psychotic Symptoms in Dementia
DRUG INVESTIGATED EFFICACY* COMMENT

Case reports and uncontrolled trials

Chlorpromazine76 38/46 Global improvement in behavior; compares oral versus parenteral administration
Haloperidol89 17/18 Global improvement in behavior and psychotic symptoms
Loxapine 14 3/5 Global improvement; 7/12 patients dropped out 2° side-effects or medical complications
Pimozide43 4/4 Global improvement in behavior and psychotic symptoms
Thioridazine34 87/ llO Global improvement; inpatients and outpatients; mixed diagnoses
Thioridazine 16 33/40 Global improvement in agitation !:l:l
Thiothixene 12 12/26 Global improvement; some psychotic and behavioral symptoms demonstrated specific improvement 0
tl:I

Controlled Trials
z
tri
Acetophenazine31 13/19 Global improvement in hyperactive behaviors; greater improvement with less severe initial symp-
toms; mixed diagnoses ~
Haloperidol85 819 Global improvement; 6/9 placebo-treated patients also improved ~
Thiothixene65 13/22 Global improvement; ll/20 placebo-treated patients also improved C"J
C"J
Trifluoperazine30 4/18 Global clinical improvement; significant side effects in approximately 40% of patients
>
z
l;j

t1
t=
::a
:<
.._
t'l
"'t;l
 zt"1
c::
e5t""
t"1
:::i
....
(J
Vl

~
Comparative Trials 0
Chlormethiazole versus Thioridazine4 60 Greater global and specific improvement with chlormethiazole than with thioridazine ;>
Chlorpromazine versus Reserpine- 64/80 Global improvement in all treated patients, including placebo; untreated patients worsened ...,t""
Pipradol versus Opium 1 t"1

"
~<
Haloperidol versus Cis(Z)-clopen- 40 Greater global and specific (motor activity) improvement with cis(Z)-clopenthixol
thixol27
Haloperidol versus Loxapine59 15/61 Approximately equal global and specific improvement with both drugs; both greater improvement t"1
than placebo-treated controls
Haloperidol versus Thioridazine83
Haloperidol versus Thioridazine 21
46
40
Both drugs globally effective, but haloperidol effective over a broader range of specific symptoms
Both drugs globally effective, but greater specific improvement with thioridazine
~
Haloperidol versus Thioridazine 73 56 Both drugs globally effective, but greater specific improvement with haloperidol; haloperidol better
~
~
tolerated; outpatients t"1
Haloperidol versus Thioridazine84 16 Both drugs globally effective; thioridazine better tolerated ~
Vl
Haloperidol versus Trifluoperazine48 39/54 Both drugs globally effective; greater specific improvement with trifluoperazine
Thioridazine versus Diazepam 20 40 Greater global and specific improvement in behavioral symptoms with thioridazine than with di-
azepam
Thioridazine versus Loxapine6 27/53 Global improvement with active drugs greater than placebo, but not statistically significant; greater
improvement with greater initial severity of symptoms

*Efficacy = number improved by author's criteria/number studied

NI
0
......
202 NEUROLEPTICS AND ALTERNATIVE TREATMENTS

tent with the theoretical hypothesis of cholinergic deficiency in AD (and

possibly other dementias) and the known anticholinergic effects of many
neuroleptics, especially low-potency agents. Lastly, neuroleptics are not ef-
fective for the core cognitive symptoms of dementia and their related
effects. 66 · 75
In several recent studies with superior research design, 6 • 48 · 59 • 84 ap-
proximately one third of patients demonstrated substantial improvement
with neuroleptic treatment, although patients treated with placebo im-
proved as well. Specific target symptoms--delusions, hallucinations, and
severe or aggressive agitation- responded with greater improvement to ac-
tive drug than to placebo. In general, the greater the initial severity of
symptoms, the greater the improvement noted. An exception to this trend
was observed for some circumscribed delusions which exhibited consider-
able resistance to neuroleptic treatment and rarely responded fully. 66 Sim-
ilarly, repetitive, nonaggressive behaviors responded poorly to neuroleptics
in some studies. 66 • 75
In summary, judicious use of neuroleptics may be indicated in AD and
other dementias for the management of well-delineated specific psychotic
symptoms (delusions, hallucinations) or severe agitation, particularly when
aggressive behaviors are involved. Clinicians should expect modest rather
than dramatic improvement in these target symptoms, whereas no consis-
tent improvement should be expected in other troublesome behaviors or in
cognitive performance.
Delirium
Delirium is often superimposed on dementia and constitutes an impor-
tant differential diagnosis of behavioral and psychotic symptoms. Although
the cardinal rule for the management of delirium is to discover and correct
the underlying etiology, adjunctive symptomatic therapy is often necessary.
Neuroleptics, especially high-potency agents, are commonly used to reduce
the disruptive impact of psychotic and behavioral symptoms while defini-
tive treatment proceeds. Overall, the consensus is that such therapy, in
combination with supportive medical and environmental interventions, is
effective. 46 However, it should be noted that this treatment approach is
empiric. Controlled and comparative trials of neuroleptics and other thera-
peutic agents for this purpose have not been published. Consequently,
there is no evidence to suggest that one neuroleptic is inherently more ef-
fective than another. However, the potential for side effects, particularly
anticholinergic effects, 46 • 66 to complicate the diagnosis and definitive treat-
ment of delirium is considerable. Thus, side effect profile becomes the ma-
jor determinant of choice of drug; high-potency neuroleptics would be
preferred.

CONTRAINDICATIONS

Few absolute contraindications to neuroleptic use exist. However,

neuroleptics produce a broad spectrum of side-effects and drug interactions
that might influence neuroleptic choice, limit neuroleptic use, or constitute
ROBIN E. W RAGG AND DILIP V. }ESTE 203
a relative contraindication in any given patient, especially in those with
preexisting medical disorders . In general, the prevalence of such disorders
is higher in the elderly.
Patients with chronic obstructive pulmonary disease, urinary reten-
tion, narrow-angle glaucoma, and constipation may find their conditions ex-
acerbated by the anticholinergic effects of neuroleptics. Patients with
coronary artery disease or arrhythmias may suffer complications from al-
pha,-adrenergic blockade. Parkinson's disease may be exacerbated by the
D -2 antagonist effects of all neuroleptics. Similarly, there is a theoretical
consideration that any neuroleptic may lower the seizure threshold and in-
crease seizure frequency in patients with pre-existing seizure disorders;
however, this is rarely observed in clinical practice. 45 Finally, weight gain,
which is presumed secondary to histamine H 1 antagonist effects, may
worsen obesity and complicate the successful management of many other
medical disorders .

SPECIFIC SIDE EFFECTS

Sedation
Sedation is a consequence of histamine H 1 blockade; this property is
associated with all neuroleptics, but particularly with low-potency agents .
It is such a common effect of neuroleptics as to be frequently overlooked.
At times, sedation is considered as much a therapeutic effect as an adverse
effect, especially in the treatment of agitation. However, in the elderly pa-
tient, neuroleptic-induced sedation has been associated with increased risk
of falls and fractures. 67 Furthermore, sedation aggravates pre-existing cog-
nitive dysfunction, which may further exacerbate problem behaviors .
Extrapyramidal Symptoms
Extrapyramidal side effects are typically classified into four groups:
acute dystonic reactions, akathisia, parkinsonism, and late-onset dyskinetic
disorders. 45 There is no evidence that the elderly are at increased risk for
acute dystonic reactions, an adverse effect generally associated with young
men. However, tardive dystonia, late-onset or persistent dystonia, occurs
with similar frequency across age differences . Older patients are more
likely to exhibit focal or segmented symptoms than the generalized symp-
toms seen in younger patients. 38
Akathisia is a potentially important adverse effect of neuroleptics in
the demented elderly. Although evidence suggests it is common in all age
groups, it is frequently under-recognized. Its diagnosis relies heavily on
subjective report, 90 which may be impaired in this population. It is possible
that some cases of repetitive, nonaggressive behaviors which are poorly re-
sponsive to neuroleptics actually represent akathisia in these patients. 45 In
such instances, reduction or withdrawal of neuroleptics would be indicated.
Other treatment options would include utilizing anticholinergic and antihis-
taminic drugs, though these are often ineffective for akathisia and may pose
additional problems in the elderly demented patient.
Neuroleptic-induced parkinsonism is phenomenologically identical to
204 ROBIN E. WRAGG AND DILIP V. }ESTE

idiopathic Parkinson's syndrome. Elderly patients, and perhaps especially

demented patients, 58 appear to be at greater risk for developing this side-
effect, although there is some evidence to suggest that the inverse may be
true. 55 Whether this propensity is secondary to underlying, unrecognized
idiopathic Parkinson's syndrome that is exacerbated by neuroleptics 45 or to
other age-related central nervous system (CNS) changes, such as a decrease
in dopamine receptors in the caudate nucleus, that are predisposing87 is
unclear. Anticholinergic drugs, although effective treatment for neurolep-
tic-induced parkinsonism, may predispose to other adverse effects in the
elderly. Balancing the therapeutic and adverse effects of combined neuro-
leptic and anticholinergic drug treatment is integral to successful man-
agement.
Tardive dyskinesia (TD) occurs with higher prevalence in the elderly.
This increased prevalence is attributable to several factors. First, there ap-
pears to be an increased susceptibility to TD with aging that is not related
to either greater amounts of neuroleptics received by the elderly or to
longer history of neuroleptic treatment.40 However, several studies report
that the elderly develop higher serum levels of neuroleptics on comparable
doses than do younger patients, 37· 49 · 93 which may be a predisposing factor.
In addition, central mechanisms such as neuronal damage, changes in the
number and sensitivity of receptors, and reduced efficiency of homeostatic
processes 40 in the elderly may also contribute to increased risk of TD. The
precise mechanisms by which these factors may act are not clearly under-
stood. Second, TD appears to demonstrate greater persistence in this age
group once it develops. 40 Younger subjects show improvement in approxi-
mately 80 per cent of cases after neuroleptic withdrawal, whereas older
(greater than 55 years) subjects fail to improve more than 50 per cent of
the time. 82 Demented elderly patients who receive neuroleptics for behav-
ioral and psychotic symptoms may constitute a group at special risk for per-
sistent TD .
TD may also go unrecognized or be misinterpreted as motor restless-
ness or agitation. Localization and severity of TD symptoms vary with age .
Older patients are more likely to have orofacial dyskinesias, whereas youn-
ger patients are more likely to exhibit limb dyskinesias. 40 TD also tends to
become more severe with aging, including a tendency to spread to pre-
viously uninvolved areas of the body.
A problem only recently classified as an extrapyramidal symptom is the
neuroleptic malignant syndrome (NMS). Current thought is evolving to
consider this problem as a severe extrapyramidal symptom with secondary
medical complications. 45 Traditionally, NMS has been thought to occur pre-
dominantly in young patients. However, recently, NMS has been reported
in a number of elderly patients, 2 · 77 including two with AD. In one of these
cases, the patient presented for hospitalization because of agitation and
paranoid ideation. 77 Treatment with haloperidol resulted in the typical clin-
ical signs of NMS- altered sensorium, fever, muscle hypertonicity- as well
as the expected laboratory abnormalities, all of which resolved with with-
drawal of haloperidol and conservative, supportive medical management.
The author hypothesizes that the demented elderly are theoretically at in-
creased risk because of reductions in dopamine concentrations in the basal
ganglia and hypothalamus. Furthermore, NMS may be underdiagnosed be-
NEUROLEPTICS AND ALTERNATIVE TREATMENTS 205
cause alterations in behavior and mental status are attributed to dementia
per se. Further research is needed to confirm these observations and
hypotheses.
Anticholinergic Effects
Most neuroleptics antagonize acetylcholinergic receptors centrally and
peripherally resulting in a panoply of adverse effects. Serious clinical effects
are typically seen at high doses of low-potency neuroleptics or when neuro-
leptics are used in combination with other anticholinergic drugs including
antidepressants and antiparkinson agents. Of particular concern in the de-
mented elderly patient is the development of anticholinergic delirium
which, in its early stages, may be mistaken for worsening of the cognitive,
behavioral, or psychotic symptoms associated with dementia. Lack of rec-
ognition may lead to mismanagement, including continued or increased use
of anticholinergic agents.
Cardiovascular Effects
Neuroleptic-induced cardiovascular effects in the demented elderly in-
clude hypotension secondary to alpha-adrenergic blockade, tachycardia sec-
ondary to anticholinergic effects and increased circulating catecholamines,
and altered conduction and other arrhythmias that appear to be related
to altered potassium metabolism. 57 The risks are greatest for the patient
who may require high medication doses for symptom control or with pre-
existing medical risk factors, especially cardiovascular disease or those
requiring medications subject to drug interactions. Neuroleptic-induced
hypotension (orthostatic or persistent) has been implicated in a higher inci-
dence of falls leading to hip fracture in the elderly. 67 Tachycardia and
rhythm disturbances may limit exercise tolerance predisposing to further
cardiac risk. Careful pretreatment assessment, including an electrocardio-
gram, is therefore advisable.
Other Medical Effects
Other medical effects of neuroleptics, though not necessarily more fre-
quent than in younger patients, may carry different implications for differ-
ential diagnosis and management in the elderly. Neuroleptics may cause
agranulocytosis in the elderly. This effect is unpredictable and potentially
life-threatening, but recovery is usual and actual mortality is uncommon.
Traditionally, this has been considered an adverse effect limited to the phe-
nothiazines. However, recently a case of neutropenia secondary to haloper-
idol was reported in an elderly woman. 42 Neuroleptic-induced neutropenia
resolves with discontinuation of the drug; however, rechallenge generally
leads to recurrence so that a change to an agent of different class is recom-
mended.
Hepatotoxicity is another adverse effect usually associated with the
phenothiazines but reported to occur with all classes of neuroleptics. Al-
though rare (incidence around 1 per cent), 45 it is of concern in the elderly
because of the potential to aggravate the already decreased effectiveness of
metabolism of drugs secondary to age-related changes in hepatic enzyme
activity and blood flow. 86
Other potential neuroleptic-induced effects of concern in the elderly
206 ROBIN E. WRAGG AND DILIP V . JESTE

include sexual dysfunction (impotence and retrograde ejaculation); ophthal-

mologic effects, specifically retinopathy, lenticular and corneal deposits,
and possibly cataracts; and dermatologic complaints such as photosensitivity
and benign skin rashes. All of these effects are more likely to occur with
the low-potency phenothiazines rather than with high-potency agents.
Finally, neuroleptics are alleged to contribute to sudden death in some
patients by promoting aspiration, ventricular arrhythmia, or hypotension.
Although the elderly appear to be at greater risk of each of these effects
independently, the evidence to support a measurably increased risk of sud-
den death related to neuroleptics is sparse. 45

ADJUNCTS AND ALTERNATIVES TO NEUROLEPTIC

TREATMENT
Benzodiazepines
A variety of benzodiazepines have been demonstrated to be effective
for reducing agitation, but not specific psychotic symptoms, in both uncon-
trolled and controlled studies. 61 • 70 · 75 However, in comparative treatment
trials, neuroleptics have been superior to benzodiazepines in efficacy. This
has been especially true the greater the degree of dementia or
agitation. 70 · 75 As with neuroleptics, all benzodiazepines appear to be of
comparable efficacy although short-acting benzodiazepines, such as oxaze-
pam or lorazepam, are generally preferred in the elderly because of a de-
creased risk of drug accumulation or drug interactions.
Beta-blockers
Propranolol has been reported to be effective in reducing agitated, ag-
gressive, and impulsive behaviors in patients with organic mental disor-
ders, typically secondary to trauma or CNS infection. 29 • 94 Though most of
the data are derived from uncontrolled studies in younger adults, several
series of case reports suggest similar positive therapeutic results in elderly
demented patients. 36· 60 Generally, high doses, exceeding 100 mg per day,
have been required for efficacy although some patients have responded in
the range of 60 mg per day. 29· 36• 60· 94 Cardiovascular side effects and drug-
drug interactions constitute the major complications that have limited this
use of propranolol. 70 Double-blind, controlled treatment or comparative tri-
als have not been reported in demented elderly patients. 75 Other beta-
blockers have not been extensively studied.
Calcium-channel blockers
Although, on the basis of case reports, these agents appear promising
in the control of behavioral and psychotic symptoms in mania and some
other psychoses, there is currently insufficient evidence to determine
whether these drugs might have similar utility in control of behavioral and
psychotic symptoms in the demented elderly. Further clinical and research
reports are necessary to evaluate their usefulness for this purpose.
Carbamazepine
Considerable evidence suggests that carbamazepine, in addition to its
anticonvulsant efficacy, is effective in the treatment of primary psychiatric
NEUROLEPTICS AND ALTERNATIVE TREATMENTS 207
disorders, particularly bipolar affective disorder. Some reports also suggest
beneficial effects in a variety of organic brain disorders, especially in reduc-
ing affective lability, aggressive behaviors, and socially inappropriate
behaviors attributable to temporal lobe 70 or frontal lobe52 pathology. Dou-
ble-blind, controlled, and comparative investigations to specifically evalu-
ate the efficacy of carbamazepine in controlling similar symptoms in the
dementias have not been published. Such studies are required before rec-
ommending its use solely for this purpose, especially as carbamazepine
side-effects may contribute to cognitive impairment and disturbances of
motor behavior. 70

Lithium
Lithium carbonate is unquestionably effective in reducing aggressive-
ness, agitation, and irritability associated with bipolar affective disorder. It
has also received some use for control of similar symptoms in patients with
organic mental disorders and impulse control disorders though with less
convincing evidence of efficacy. 70 Indeed, published reports suggest that it
may be ineffective for this purpose in AD; 91 however, the number of cases
reported is very small, and the area has not received systematic study.
There is also the potential for lithium to contribute to cognitive deteriora-
tion either independently, secondary to increased drug levels, 35 or in con-
junction with neuroleptic treatment, despite conventional doses and
normal serum levels. 54 Consequently, its use seems best reserved for pa-
tients in whom a clear affective component to behavioral and psychotic
symptoms exists or for those who are refractory to other treatments.

Trazodone
Several case reports 81 · 88 and an uncontrolled clinical trial56 support a
positive therapeutic effect for trazodone in control of agitation in elderly
demented patients. Doses required to achieve this effect are typically in
the range of 200 to 400 mg per day. 56• 75· 81• 88 The mechanism by which tra-
zodone is effective in this regard is unknown. The effect does not appear
to be related to antidepressant or general sedative properties, but rather to
calming or taming effects observed in animal models that are associated
with serotonin re-uptake blockade. 75
Electroconvulsive Therapy
In recent years, electroconvulsive therapy (ECT) has been used pre-
dominantly for the treatment of major depression refractory to antide-
pressant therapy or with life-threatening neurovegetative symptoms or
self-destructive behaviors. In earlier years, ECT had been more widely uti-
lized in the treatment of undifferentiated or refractory psychoses. No sys-
tematic investigation of its efficacy for the treatment of psychotic symptoms
in the dementias has been published. However, as there are relatively few
absolute contraindications to ECT and few serious adverse effects, it may
be an appropriate modality to consider in cases of severe behavioral and
psychotic symptoms in whom other therapies are either ineffective or con-
traindicated. Further research to evaluate the relative risks and benefits of
this approach is warranted.
208 ROBIN E. WRAGG AND DILIP V. }ESTE

Behavioral and Psychosocial Therapies

Agitation and other behavioral symptoms in the demented elderly are
often linked to less than ideal environmental circumstances or a major
change in an environment to which the patient has become
accustomed. 15· 19· 33• 50· 92 Behavioral interventions designed to overcome
these problems have been demonstrated to reduce undesirable
behaviors. 15• 33· 92 Several small studies also suggest that reductions in the
expression of psychotic symptoms can be achieved by similar methods. 28 · 62
Presumably, interventions designed to achieve an optimal environment
also enhance the quality of life for demented patients though this has not
been specifically demonstrated. 7• 15 Clearly, there are few conceivable con-
traindications to behavioral therapies; yet, some reservations may remain.
Some consider behavior modification programs to raise ethical concerns.
Such programs are commonly quite labor-intensive and, therefore, expen-
sive, which may limit their widespread application. Further research is
needed to more clearly identify which patients in which settings are most
likely to benefit.
Supportive Psychotherapy
The decision to use pharmacotherapy or other somatic treatments for
symptomatic relief must necessarily balance the potential benefits of im-
provement against impact of the symptoms on the patient and caregiver,
the likelihood of improvement, and the ethical considerations of further
treatment. The precise valence of these items must be decided individually
for each patient evaluation. A close working alliance, tempered by mutual
positive regard, with both the patient and the caregiver(s) is essential to
understanding and addressing these issues productively. 7• 50· 62 Moreover,
although there may be no effect on the dementia per se, such a supportive
relationship may well have a modulating effect on behavioral symptoms and
their impact. Adjunctive family or group therapy for caregivers may have
similar beneficial effects and enhance compliance with pharmacotherapy
and other interventions. Ultimately, supportive psychotherapy may be crit-
ical to introducing and resolving issues related to the compassionate discon-
tinuation of aggressive therapeutic interventions.

SUGGESTED GUIDELINES FOR NEUROLEPTIC USE IN

DEMENTED ELDERLY PATIENTS
Neuroleptics have a clear, but circumscribed, role in the management
of behavioral and psychotic symptoms in dementia. Target symptoms which
have been demonstrated to be responsive to neuroleptics-delusions, hal-
lucinations, severe agitation--constitute the major indication for prescrib-
ing neuroleptics. Clear identification, delineation, and documentation of
target symptoms at the initiation of therapy permits effective monitoring for
specific as well as global improvement. Target symptoms should be fre-
quently and regularly re-evaluated. Even for the clinician, use of rating
scales may facilitate systematic identification and recording of symptoms.
Several instruments are available (Symptoms of Psychosis in Alzheimer's
Disease [SPAD], 69 BEHAVE-AD, 68 Diagnostic Interview Schedule
[DIS]72).
NEUROLEPTICS AND ALTERNATIVE TREATMENTS 209
Once a decision to treat with neuroleptics has been made, treatment
should be focused and time-limited. The smallest effective dose should be
used. In fact, a recent study suggests that much smaller doses than pre-
viously thought useful may be effective. 71 Although serum neuroleptic lev-
els are less widely used and less well-correlated with treatment response
than are other drug levels, they may yield helpful information in trouble-
some cases. One should attempt to reduce the dose of neuroleptics periodi-
cally, as the course of behavioral and psychotic symptoms, treated or
untreated, is unclear in the dementias. If symptoms have resolved, neuro-
leptic therapy may be discontinued.
Adverse effects may significantly limit the therapeutic potential of neu-
roleptics. Consequently, systematic monitoring of side effects and drug in-
teractions is as important as monitoring therapeutic effect. Because
individual neuroleptic agents appear to have similar efficacy for psychotic
and behavioral symptoms in dementia, side effect profile may be the deter-
mining factor in choosing an appropriate drug. Prophylactic treatment for
extrapyramidal syndromes with anticholinergic or antihistaminic drugs
should not be routinely prescribed, but should be reserved for specific in-
dications.
Finally, the importance of a strong working alliance with both the pa-
tient and the caregiver should not be underestimated. The medicolegal and
ethical issues that apply to working with demented patients are complex.
Informed consent, in a strict sense, may not be possible. Nonetheless, cli-
nicians should attempt to ensure that patients, their families, and other care-
givers are adequately informed of the risk-benefit ratio of neuroleptic use.
In addition, routine discussion of the rationale for treatment and potential
complications communicates the importance of patient and caregiver partic-
ipation in clinical decisions. Similar consideration of compliance issues may
explain otherwise puzzling and troublesome observations such as poor
treatment response, unexpected medication toxicity, or adverse effects.

SUMMARY

Behavioral problems, and even psychotic symptoms, are universally

acknowledged as among the most distressing consequences of dementia. A
majority of patients experience either or both at some time during the
course of dementia. Agitation is so common that accurate prevalence rates
are difficult to ascertain; the available data suggest approximately 70 to 80
per cent of patients manifest this behavior in some form. Psychotic symp-
toms in some form occur less frequently, but perhaps affect up to half of
demented patients at some time.
N euroleptic medications are among the psychoactive drugs most fre-
quently prescribed for the demented elderly, yet they carry the risk of con-
siderable morbidity from side effects, both acute (extrapyramidal
syndromes, cardiovascular toxicity, anticholinergic effects) and chronic (tar-
dive dyskinesia). They are most widely used for behavioral and psychotic
symptoms; however, their efficacy for these problems is far from unequivo-
cally established.
The multiple medical problems of the elderly add to the complexity
210 ROBIN E. WRAGG AND DILIP V. JESTE

of diagnosing and managing these symptoms. Systematic delineation of the

etiology, course, and prognosis of behavioral and psychotic symptoms may
clarify the indications for such treatment. Further research on effective ad-
juncts and alternatives to neuroleptic treatment in the demented elderly
may facilitate patient management, maximizing efficacy and reducing po-
tential adverse consequences.

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Department of Psychiatry, V-116A

Veterans Administration Medical Center
3350 La Jolla Village Drive
San Diego, California 92161