CLINICAL AND RESEARCH REPORTS
Conventional vs. Newer
Antipsychotics in
Elderly Patients
Dilip V. Jeste, M.D.
Enid Rockwell, M.D.
M. Jackuelyn Harris, M.D.
James B. Lohr, M.D.
Jonathan Lacro, Pharm.D.
Elderly patients with schizophrenia and dementia patients with agitation are frequently candidates for
antipsychotic treatment. Conventional neuroleptics
have relatively little effect on negative symptoms and
may cause considerable side effects, especially in elderly patients. The authors have found a 29% cumulative annual incidence of tardive dyskinesia (TD) in
middle-aged and elderly outpatients treated with relatively low doses of conventional neuroleptics. Newer
antipsychotics are less likely to cause extrapyramidal
symptoms and may be associated with a lower risk of
TD. They are generally effective for both positive and
negative symptoms and may also improve some aspects of cognition, but these drugs have their own side
effects. Dosing requirements for elderly patients tend
to be much lower than those for younger adults. (Am
J Geriatr Psychiatry 1999; 7:70–76)

A

s the population in the United States continues to
age, physicians must become increasingly familiar
with the health care needs of elderly patients. Psychiatrists will be caring for more patients with late-life psychotic disorders and those with behavioral disorders associated with Alzheimer’s disease (AD) and other
dementing illnesses. Although the symptoms of some
mental illnesses respond to cognitive–behavior therapy
and other nonpharmacologic interventions, antipsychotic drugs remain the principal means of treating psychotic and certain other severe behavioral symptoms,
both in younger and older patients. For many years, the

choice of antipsychotic medication was limited to what
are now called conventional or typical neuroleptics,
such as haloperidol and thioridazine. Today, clinicians
also can select from newer or atypical antipsychotics,
such as clozapine, risperidone, olanzapine, and quetiapine. Choosing the appropriate medication and its dosing requires careful consideration of each drug’s effects,
including its side effects.
Conventional or Typical Neuroleptics
Conventional neuroleptics have been available for
more than 45 years, beginning with the introduction of
the low-potency agent chlorpromazine in 1952. Highpotency neuroleptics, such as haloperidol, and intermediate-potency ones, such as loxapine, became available later on. All these drugs share a common
characteristic in that they block the dopamine (especially D2) receptors in the brain. This activity confers
both benefits and drawbacks. Although conventional
neuroleptics are effective for the positive symptoms of
schizophrenia, they have relatively little effect on the
negative symptoms of this disease. They also can cause
side effects, many of which are of particular concern in
elderly patients, who are more susceptible to drug side
effects. Neuroleptic side effects include sedation, anticholinergic toxicity (which can result in urinary retention, constipation, dry mouth, glaucoma, and confusion), extrapyramidal symptoms ([EPS]; e.g.,
parkinsonism, akathisia, and dystonia), and tardive dyskinesia (TD).
TD can be troubling because of its frequently persistent nature. In young adult patients taking conventional neuroleptics, the annual cumulative incidence of
TD is 4% to 5%.1 To determine the incidence of this side
effect in middle-aged and elderly subjects, we studied
439 outpatients (with a mean age of 65 years) in whom
antipsychotic treatment was indicated (Figure 1). Earlier
reports from our group2,3 had included 266 and 307 of
these patients, respectively. Twenty-eight percent of the
patients had a primary diagnosis of dementia with psychotic symptoms or other severe behavioral disturbances; 22% had schizophrenia; 18% had a mood disorder; and the remainder had other diagnoses. At the
time of study enrollment, a majority of the patients had

Received February 24, 1997; revised August 10, 1997; accepted August 11, 1997. From the Department of Psychiatry, University of California, San
Diego, and the San Diego Veterans Affairs Medical Center. Address correspondence to Dr. Jeste, Psychiatry Service, 116A1, Veterans Affairs Medical
Center, 3350 La Jolla Village Drive, San Diego, CA 92161, e-mail: Dilip_Jeste@GP-Post.ucsd.edu

70

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Jeste et al.
been treated with neuroleptics for less than 1 month;
the median duration of lifetime antipsychotic drug exposure was 27 days. After study enrollment, most of the
patients were treated with conventional neuroleptics,
mainly haloperidol or thioridazine, at relatively low
doses (usually less than 150 mg chlorpromazine-equivalent daily). Patients were assessed at baseline, 1 month,
3 months, and every 3 months thereafter. The diagnosis
of TD was based on the Schooler-Kane4 criteria, using
the Abnormal Involuntary Movement Scale (AIMS).5
With 12 months of neuroleptic treatment, TD developed in 28.8% (95% confidence interval [CI]: 26.1%–
31.5%) of the patients. At 24 and 36 months, the mean
(with 95% CI) cumulative incidence of this side effect
was 50.1% (46.7%–53.5%) and 63.1% (59.3%–66.9%), respectively, demonstrating the higher risk of TD in middle-aged and elderly patients even with low doses of
conventional neuroleptics.
By discontinuing neuroleptic treatment, TD may be
avoided or reversed. In patients with behavioral disturbances of dementia, drug withdrawal or at least dose
reduction does not present major problems in a majority of cases;6 indeed, in appropriate patients, neuroleptics may be slowly tapered after a few months to deter-

mine whether they are still needed to control the
behavioral symptoms. In patients with schizophrenia,
however, drug withdrawal is usually difficult. A recent
literature review of 66 studies including a total of 4,356
patients with schizophrenia or schizoaffective disorder
showed that relapse rate over a mean follow-up period
of 9.7 months was 53% when the antipsychotic drugs
were withdrawn and 16% when the drugs were maintained.7 Although most of these studies were conducted
in young adults with schizophrenia, the rates of relapse
after neuroleptic withdrawal appeared to be similar in
the investigations that involved elderly patients.8
With conventional neuroleptics, clinicians face the
following dilemma: to continue using a drug associated
with serious side effects or discontinue the drug and
possibly trigger a relapse. Maintaining patients on flexible, individualized, low doses of conventional neuroleptics may prevent or delay the appearance of side effects while continuing to control the psychotic
symptoms. Another possible solution is to prescribe
newer antipsychotic medications, which are usually
more effective and have fewer side effects than conventional neuroleptics.
Newer or Atypical Antipsychotics

FIGURE 1.

Incidence of tardive dyskinesia (TD) in 439
middle-aged and elderly outpatients (age Ͼ45)
over a 36-month period: means with 95%
confidence intervals (CI)

Am J Geriatr Psychiatry 7:1, Winter 1999

At present, four newer antipsychotic drugs—clozapine, risperidone, olanzapine, and quetiapine—have
been approved for use in the United States. Several
other newer antipsychotics, including ziprasidone and
zotepine are currently awaiting Food and Drug Administration (FDA) approval.
Unlike conventional neuroleptics, the atypical ones
are potent central serotonin antagonists in addition to
being central dopamine-receptor antagonists. This activity profile apparently confers several advantages with
respect to both efficacy and safety. In young and middleaged patients with schizophrenia, serotonin–dopamine
antagonists have generally been shown to be effective
for both the positive and negative symptoms of the disease.9–12 These drugs are associated with a lower incidence of EPS than conventional neuroleptics. The low
risk of TD in patients taking clozapine is well established.13 The incidence of TD with other atypical antipsychotics is also likely to be lower than that with conventional neuroleptics, given that EPS has been found
to be a risk factor for TD in elderly patients.2,14 Nonetheless, the determination of exact risk of TD with these
newer drugs requires long-term studies. An intriguing

71

Conventional vs. Newer Antipsychotics
aspect of the atypical antipsychotics is their potential
for enhancing cognition, a particularly useful effect in
older patients with schizophrenia. In the following discussion, we will refer only to published articles, rather
than to abstracts or presentations.
Clozapine. Although clozapine has been available in
the United States since the late 1980s,9 well controlled
published studies of its use in elderly patients have been
rare. Data from open, uncontrolled trials in older psychiatric patients indicate that clozapine is useful for
controlling treatment-resistant psychotic symptoms and
managing patients with severe TD.15,16
Although clozapine is effective in elderly patients,
side effects limit its use in this patient population. Patients taking this drug are at risk for leukopenia and
even agranulocytosis; this risk necessitates weekly
blood monitoring. Elderly outpatients may have difficulty complying with the need for weekly blood draws.
Clozapine can lower the seizure threshold and can also
cause sedation and confusion. In patients with dementia or glaucoma or in men with prostatic hypertrophy,
the anticholinergic side effects of this drug can be particularly troublesome.
Despite its side effects, clozapine may be indicated
for some elderly patients, such as Parkinson’s disease
patients with psychotic symptoms,17,18 patients with
chronic psychotic disorders that do not respond to
other antipsychotic medications, or those with severe
TD. For these patients, recommended starting doses are
much lower than those for younger patients: 6.25 mg
to 12.5 mg/day, with increases of no more than 6.25 mg
to 12.5 mg once or twice a week. Maintenance doses
should generally be 50 mg to 100 mg/day.
Risperidone. Beginning with the report by Marder
and Meibach,10 numerous published double-blind investigations have established the significantly better efficacy and tolerability of risperidone compared with haloperidol in younger adults. Although published data from
double-blind, placebo-controlled trials of risperidone in
elderly patients are not yet available, we have studied
risperidone in open studies of patients age 45 to 100
years.19 Most enrolled patients had schizophrenia or related psychoses, such as delusional disorder, and the
rest had psychotic symptoms associated with dementia.
Patients received low doses of risperidone, usually less
than 3 mg/day. Of the 53 enrolled patients, 40 (76%)
experienced a noticeable improvement of symptoms.

72

Improvement in the positive symptoms of schizophrenia, such as delusions and hallucinations, was apparent
within the first 6 weeks after treatment was started.
Negative-symptom (e.g., social withdrawal, blunted affect, and apathy) improvement was apparent only after
6 to 10 weeks of treatment. We have reviewed the literature elsewhere19,20 on the use of risperidone in elderly patients.
We also examined the effects of risperidone on
global cognition in 19 of our patients, most with schizophrenia.19 The mean age (‫ע‬standard deviation [SD]) of
the patients was 65‫ 41ע‬years. Treatment with risperidone for a mean of 11‫ 7ע‬weeks was associated with a
significant increase in the mean Mini-Mental State Exam
(MMSE)21 score (24 before treatment to 28 after treatment; P‫ .)500.0ס‬Interestingly, open-label treatment
with conventional neuroleptics given for 3 months in
relatively low dosages to 37 age-, gender-, and diagnosiscomparable patients in our population resulted in no
significant change in the mean MMSE scores.22 Berman
and colleagues23 have also reported cognitive improvement with low-dose risperidone given to elderly psychotic patients in an open trial. In a recent report on
younger adults with chronic schizophrenia, Green and
colleagues24 found significant improvement in performance on tests of verbal working memory with risperidone, as compared with haloperidol. Such findings do
not necessarily suggest that risperidone directly enhances cognition in patients with schizophrenia. The
effects on cognition may be indirect, resulting from its
favorable effects on the positive and negative symptoms
of schizophrenia and its low incidence of EPS at the
doses used in these studies. Nonetheless, a positive effect on cognition may be of particular importance in
light of recent data suggesting an association between
cognitive performance and functioning in daily life.25,26
It is interesting to note that the cognitive effects of
clozapine have been reported to be somewhat mixed.
Whereas performance on tests of verbal fluency and graphomotor speed was improved, there was significant
worsening of the visual memory and executive, frontal
ability.27 The likely explanation is that clozapine, as an
atypical antipsychotic, may improve cognition, but its
high anticholinergic and frontal D1 receptor-blocking
activity may serve to impair certain aspects of neuropsychological performance, but there is no evidence to
suggest that any of the atypical antipsychotics affect
cognition in patients with dementia.
The more common side effects associated with ris-

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Jeste et al.
peridone use in elderly patients are postural hypotension, sedation, and EPS. These side effects (especially
EPS) are dose-related, suggesting a need for caution in
raising the dose.
Starting and maintenance dosages of risperidone in
elderly patients are much lower than those recommended for younger patients. A starting dose of 0.25
mg to 0.5 mg/day is appropriate for older patients. The
dose should be increased by no more than 0.25 mg to
0.5 mg once or twice per week, generally up to a maximum daily dosage of 1.0 to 2.5 mg. Patients with dementia, Parkinson’s disease, or significant hypotension
should usually not receive more than 1 mg/day of risperidone.
Other Atypical Antipsychotics
The published data on other atypical antipsychotics
in elderly patients are limited.
Olanzapine. Olanzapine was approved by the FDA for
clinical use late in 1996. A number of double-blind, controlled studies, such as an international collaborative
trial involving nearly 2,000 mostly young and middleaged adults28 have shown a superior and broaderspectrum efficacy of olanzapine in the treatment of
schizophrenia, schizoaffective, and schizophreniform
disorders, along with a significantly better safety profile
than haloperidol. There is also one report of lower incidence of TD with olanzapine than with haloperidol
among non-elderly patients.29 The main side effects of
olanzapine include sedation, dizziness, weight gain, and
minimal anticholinergic reactions. The published data
with olanzapine in elderly patients are, however, restricted. In one open-label study,30 15 parkinsonian patients (without dementia) with drug-induced psychosis
were treated successfully with olanzapine at doses of 1
mg to 15 mg/day (mean: 7 mg). One patient discontinued treatment because of drowsiness.
We recommend that the starting dose of olanzapine
in elderly patients be 1 mg to 5 mg (average 2.5 mg)
daily, and the maintenance dose be 5 mg to 15 mg daily.
Quetiapine. Quetiapine was introduced into clinical
practice in 1997. It has been found, in large-scale, double-blind investigations, to be significantly more effective and better tolerated than haloperidol in patients
with schizophrenia.31 It has an exceptionally low potential for EPS even at higher doses and little anticholin-

Am J Geriatr Psychiatry 7:1, Winter 1999

ergic or prolactin-elevating action. The principal adverse effects include drowsiness, postural hypotension,
and (in long-term studies of dogs, but not reported in
humans) lenticular opacities. To date, several abstracts
but no published articles on quetiapine in elderly patients are available.
On the basis of the clinical literature, the recommended starting doses of quetiapine in elderly patients
would be 12.5 mg to 25 mg daily, with the optimal target dose being 75 mg to 125 mg per day.
Others. A number of other novel antipsychotic agents
are currently in various stages of investigation. Some of
these, such as ziprasidone, are expected to be approved
shortly. At this time, published articles on the use of
these drugs in the geriatric population are practically
nonexistent.
Table 1 summarizes the recommended starting and
maintenance doses (for elderly patients) of the two
most commonly prescribed conventional neuroleptics
and the four currently available atypical antipsychotics.
It is expected that there will be an increasing number of investigations of the efficacy and tolerability of
the various atypical antipsychotics in geriatric patients,
including studies with double-blind design and large
sample sizes.
Switching From a Conventional Neuroleptic
to a Newer Antipsychotic
Because of its side effects, clozapine is used in psychiatry predominantly for patients with treatment-resistant schizophrenia or severe TD. Other atypical antipsychotics, such as risperidone, olanzapine, or quetiapine,
TABLE 1.

Usual recommended doses of common
antipsychotic drugs for elderly patients, mg/day

Antipsychotic

Starting
Dose

Maintenance
Dose

Haloperidol
Thioridazine
Clozapine
Risperidone
Olanzapine
Quetiapine

0.25–0.5
10–25
6.25–12.5
0.25–0.5
1–5
12.5–25

1–3.5
50–100
50–100
1–2.5
5–15
75–125

Note: Patients with major comorbidity, such as dementia or
other serious physical illnesses, would need doses at the lower end
of the respective ranges, whereas patients with early-onset
schizophrenia without significant comorbidity would require doses
at the higher end of the ranges. The recommended doses represent
averages. Individual patients may need lower or higher doses than
those shown here.

73

Conventional vs. Newer Antipsychotics
should, however, also be considered for patients who
require antipsychotic treatment for the first time.
Newer antipsychotics are also indicated when patients do not respond to conventional neuroleptics or
experience distressing side effects. The method for
switching from a conventional neuroleptic to a newer
atypical antipsychotic depends on the reason for the
switch (Figure 2). (Needless to say, such a switch may
not be warranted in a patient who has responded optimally to a conventional neuroleptic without side effects and who only needs neuroleptic treatment for a
relatively short period.)
A:

If the conventional neuroleptic is ineffective, the
dose of the current drug should be maintained
while that of the newer antipsychotic is slowly in-

FIGURE 2.

74

B:

creased until the optimal maintenance dose is
reached. At that point, the dose of the conventional
neuroleptic can be slowly decreased and ultimately
discontinued.
For patients with moderate or distressing side effects, such as EPS, the dose of the conventional neuroleptic should be slowly tapered while the dose
of the newer antipsychotic is slowly increased.

Thus, in both scenarios, A and B (see Figure 2), the
conventional neuroleptic should not be stopped suddenly; otherwise, there may be a risk of relapse. In all
cases in which a patient was receiving an anticholinergic drug along with the conventional neuroleptic, the
anticholinergic agent may be continued for a few days
after the neuroleptic-withdrawal. This reduces the

Suggested methods of switching from a conventional neuroleptic to a newer, atypical antipsychotic,
according to the reason for the switch

Am J Geriatr Psychiatry 7:1, Winter 1999

Jeste et al.
chances of cholinergic rebound, with resultant nausea,
vomiting, and other symptoms.
C:

If a patient is experiencing life-threatening side effects, such as neuroleptic malignant syndrome, the
offending neuroleptic drug must be discontinued
immediately. The newer antipsychotic may then be
started and slowly titrated to the most effective
dose.
Whenever possible, once-daily dosing is preferred to a multiple daily dosing regimen. Oncedaily dosing increases the likelihood of compliance,
particularly in patients with chronic schizophrenia,
who typically require antipsychotic medication for
most of their life. Patients taking medication once
daily are, however, at an increased risk for side effects such as sedation or postural hypotension after
drug administration during the first few days. To
reduce this problem, the clinician may prescribe
smaller, divided doses initially, then switch to a
once-daily regimen after a steady-state drug level is
achieved.
Pharmacoeconomics

The atypical antipsychotics are more expensive
than the conventional drugs. At the same time, studies
in younger adults show that the newer agents may be
more cost-effective in the longer term because they reduce the number and length of hospitalizations.32 Furthermore, the lower incidence of EPS and probably of
TD may result in better compliance and an improved
quality of life for the patients. Thus, the overall cost–
benefit ratio would usually seem to favor the atypical
antipsychotics over the typical ones. There is, however,
a need for well-designed pharmacoeconomic studies
comparing typical and atypical antipsychotics, as sug-

gested by Hargreaves and Shumway,33 especially for elderly patients.

CONCLUSIONS
The availability of the newer atypical antipsychotic
drugs offers clinicians an additional means of treating
the symptoms of schizophrenia and other psychotic disorders as well as severe behavioral disturbances in patients with dementia. These drugs may be particularly
appropriate for elderly patients, who are more susceptible to EPS and TD associated with conventional
agents. The different atypical antipsychotics do have
their own side effects and other limitations. Clinicians
who prescribe antipsychotics for elderly patients
should start with a low initial dose, increasing this dose
slowly until the lowest effective dose is reached. Polypharmacy is also a concern among elderly patients, who
are often being treated for various medical problems.
Clinicians should try to avoid prescribing multiple
drugs with anticholinergic or sedative effects. It is important to remember that although antipsychotics provide symptomatic relief, they do not cure the underlying illness. Thus a comprehensive treatment approach
for psychotic and other severe behavioral disorders
must combine drug therapy with appropriate psychosocial interventions.
This work was presented, in part, at the symposium, “Pharmacotherapy and the Geriatric Patient,”
held at the 149th Annual Meeting of the American
Psychiatric Association, May 5, 1996, New York, NY.
The work was supported, in part, by National Institute of Mental Health grants MH49671, MH45131,
MH43693, MH51459, and by the Department of Veterans Affairs.

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