Classic antipsychotics are widely used in the older adult population today in an attempt to treat psychosis. In particular, the phenothiazines (i.e., Thorazine) are used to diminish the positive symptoms that accompany the presentation of schizophrenia and acute delirium. Although these types of medications, by blocking dopamine receptors, do have varied clinical utility in some individuals, they also tend to produce quite deliberating side effects. The likelihood of acute extrapyramidal reactions, such as akathesia, dystonia, and neuroleptic-induced parkinsonism is quite high, with close to 90% of all classic antipsychotic users developing these reactions. Likewise, an additional movement disorder, tardive dyskinesia, can also present as a result of typical antipsychotic use. The latter adverse reaction is not as likely to occur, as approximately 10% of phenothiazine users develop this, however, when it does present it can be extremely deliberating and often irreversible.

Thorpe reports that a variety of side effects with clozapine use, including sedation, weight gain, constipation, and dry mouth, are a result of histamine receptor antagonism and muscarinic receptor affinity. Postural hypotension is an additional side effect with serious implications for an elderly individual. A hypotensive individual tends to have recurrent lightheadedness and fainting often with extreme fatigue. Obviously, this type of side effect in the elderly takers of clozapine is serious as it increases the likelihood of falls. Thorpe reports that the most serious side effect found in the elderly users of clozapine is agranulocytosis. Because of the potential for this side effect, frequent blood monitoring is required. Blood monitoring, however, can cause a number of problems in its own right including those who have poor veins and those with high agitation levels, not to mention the high cost of a constant blood monitoring program.

Thorpe concludes his discussion of clozapine in the elderly by presenting a number of studies describing its effectiveness in this population. These studies are now presented:

1. Oberholzer et al (1992) - retrospective study of 18 elderly individuals with dementia and other

diagnoses using clozapine; 4 taken off drug cause of ineffectiveness or side

effects; mean dose=53.2mg

2. Frankenburg & Kalunian (1994) - 8 elderly patients with refractory psychoses; clozapine helpful in 6,

other 2 had neuroleptic-induced confusion, 2 had significant

hypotension

3. Pitner et al (1995) - 4 elderly with dementia or psychosis; clozapine caused significant adverse effects

in all 4, only 2 had improvement in psychosis; doses from 6.25mg to 37.5mg

4. Chengappa et al (1995) - 12 individuals over 60 years of age on clozapine; 7 stopped using cause of

postural hypotension, 1 with agranulocytosis, 1 with leukopenia (decrease in

white blood cells predisposing patient to infections); dosage up to 300mg/day

5. Salzman et al (1995) - high rate of side effects in 20 elderly individuals using clozapine; dosage mean

=210mg/day

term response to clozapine unknown as is potential risks of side effects

Subjects - 49 patients diagnosed with idiopathic PD prescribed clozapine for psychotic symptoms

-no differences in improvement rates in varying LD dose

Conclusion - clozapine use does not exacerbate motor symptoms of PD, although it also does not seem to improve

condition either; side effects did occur, but in low incidence (12%), clozapine has effectiveness

in reducing psychosis in large portion of sample

-overall authors state that results support the use of clozapine in the elderly PD population

Criticism of study - results tempered cause of retrospective nature of method

Schneider begins by discussing reasons as to why clozapine is used to treat psychosis in the elderly. She states that clozapine is appropriate for the individual when he/she is not receiving any beneficial effects from typical antipsychotics. Clozapine is also indicated when an individual cannot tolerate the acute extrapyramidal side effects of conventional neuroleptics. Schneider then proceeds to discuss the following advantages to clozapine use in the elderly:

1. Low extrapyramidal side effects (little evidence of tardive dyskinesia).

2. Ability to treat both positive and negative symptoms.

3. Little to no effect on prolactin levels (prolactin is hormone that stimulates milk production in females -

no effect on males to date)

4. Effectiveness in low doses with PD patients.

Schneider identified the following limitations of clozapine use in the elderly:

1. Anticholinergic effects, which may limit compliance to medication treatment.

2. Ability to cause hypotension.

3. High level of sedation, which may limit the amount of drug that can be administered.

4. Potential of causing agranulocytosis.

5. Potential for causing seizures.

occupancy; clozapine may also be an effective mood stabilizer

Subjects - 3 elderly men institutionalized with Bipolar I, most recent episode manic with psychotic features; all 3

noncompliant or intolerant of lithium, valproate, benzodiazepines, and conventional antipsychotics;

additional subject presentation as follows:

-Subject 1 - developed parkinsonism from previous neuroleptics, no tardive dyskinesia; CGI

score of 6 (severely ill) with elated mood, belligerence toward staff, delusions,

noncompliance with medical care, and increased energy

-Subject 2 - developed extrapyramidal side effects and tardive dyskinesia from previous

neuroleptics prior to clozapine treatment; CGI of 6 (severely ill) due to irritable mood, agitated violent behavior because of auditory hallucinations, and increased energy

-Subject 3 - had marked parkinsonism, but no tardive dyskinesia; CGI of 7 (among the most

extremely ill) due to elated mood, paranoid & grandiose delusions, increased energy,

violence to staff and patients, and intolerance to conventional antipsychotics which

tended to cause him to fall

Method - clozapine response determined by Severity of Illness rating of the Clinical Global Impression (CGI)

Scale (1-7 with 1-normal and 7-among the most extremely ill)

-evaluation of extrapyramidal side effects and tardive dyskinesia completed through clinical exam

-complete blood counts every week for 6 months, then twice a week for rest of study

-Subject 1 - 3 wks after clozapine began (12.5mg), his mood stabilized and psychosis lifted; CGI=1

(normal); these beneficial effects still existed at 12 mths

-Subject 2 - 4 wks after clozapine began (50mg morning, 62.5mg evening), CGI=2 (borderline mentally

ill); extrapyramidal side effects and tardive dyskinesia improved substantially; did have

myoclonus (typified by a brief, sudden, shock-like muscle contractions) at higher dosage,

myoclonus dissipated as dose lowered (down 12.5mg/day); remained well through first 14

mths, at this time had a severe psychotic relapse with CGI=7 (among the most extremely ill),

however an increase in clozapine (75mg each dose) dosage reduced symptamotology

considerably with CGI=2

-Subject 3 - 7 wks after clozapine began (50mg), CGI=3 (mildly ill); falls and violence nonexistent, side

effects at higher dosages (125mg) including: sedation, hypotension, & thrombocytopenia

condition continued up to 7 months, when he had a fatal stroke

-Overall - severity of illness scores improved for all three (pre-CGI mean=6.33, post-CGI mean of 2.0); all

showed marked improvement in premorbid extrapyramidal effects and tardive dyskinesia;

average response time was 5 wks; therapeutic doses varied depending on patient; side effects in

two of three patients, although both improved with lower doses; duration of beneficial effects=

11 months

Conclusion - use of clozapine in elderly bipolar patients has clinical effectiveness for acute and long-term manic

symptoms; psychotic symptoms were decreased with little occurrence of side effects, those side

effects that did exist were diminished as the dosage was reduced

small sample size

1. Factor et al (1994) - 19 PD patients with psychosis (hallucinations, paranoid delusions, or confusion

and disorientation); assessed patients at beginning of trials, 4 times in first 3 mths

on medication, & every 3 mths for next 2 yrs; used Activities of Daily Living Scale

(ADL), PD Rating Scale, Mini-Mental Status Exam (MMSE), & Brief Psychiatric

Scale (BPRS) to assess ability to care of self, Parkinsonism behaviors, cognitive

status, and psychosis; dosages varied from 6.25mg every other day to 150mg every

day; all patients had significant improvements on BPRS at first 12 mth

assessment, improvements still there on BPRS in second yr but not as substantial;

motor function improved at first, but declined over last part of study; cognitive

status scores stable over first year and a half, then declined; no changes at any

point in ADL scores; overall low side effects produced by clozapine

2. Wolters et al (1990) - double-blind, looking at treating drug-induced psychosis in 6 PD individuals

with clozapine; dosage titrated to 250mg/day; 3 taken off medication (1 from

sedative effects, 2 from drug-induced agitation/delirium, 3 who continued on

medication 2 with premorbid psychosis improved although developed delirium

3. Kahn et al (1991) - 11 PD patients, 8 with comorbid dementia that preceded onset of psychosis; 7 of

8 demented PD individuals had transient confusion due to clozapine use, the

other had such substantial confusion that he/she had to be taken off medication;

2 of 3 nondemented PD patients also had transient confusion; all patients

showed at least partial improvement in psychosis

4. Greene et al (1993) - 9 PD patients with mild dementia & 4 PD patients with severe dementia; mean

dose=67.4mg/day; all 9 with mild dementia had some benefit from clozapine,

only 1 of 4 with severe dementia improved on measure of psychosis (likely due

to discontinuation of clozapine in this group as they did not tolerate the

medication very well); only 2 individuals overall experienced delirium as a side

effect, however this dissipated in one week as the dosage was reduced

In the next section of this article, Musser and Akil present the side effects that are commonly associated with clozapine use including: sedation, weight gain, anticholinergic side effects, hypersalivation, and tachycardia. Even if these side effects are tolerated by the elderly clozapine user, the likely appearance of severe sedation, hypotension, and/or delirium greatly limit the use of this medication. A final limitation of this medication is the expense. When used in the elderly, Medicare does not always provide reimbursement for clozapine dosages, and may not even pay for the constant blood monitoring sessions that are required with administration of this drug.

Musser and Akil conclude that the benefits of clozapine overshadow the risks at least when focusing on PD patients with psychosis. They recommended an initial dose of 6.25mg/day with increases as tolerated. The authors are quick to note that the ability to predict a beneficial treatment outcome with clozapine is weak.

Intro - effectiveness of clozapine in treating psychosis in elderly patients has had little empirical research completed on it

Subjects - 10 (8-schizophrenia, 1-bipolar, 1-schizoaffective disorder), individuals diagnosed with primary psychotic

disorder who were resistant to treatment with classical antipsychotics were given clozapine

Method - Brief Psychiatric Rating Scale (BPRS) given at beginning of study (pre-clozapine) and following last

dosage; clozapine dosage began between 12.5-25mg/day and titrated up to mean of 204mg/day

effectiveness; 4 of 7 patients with improvement continued on clozapine following the study, 2 of these

eventually taken off because of side effects (1-atrial fibrillation {a chaotic or irregular impulse of the

heart}, 1-systemic lupus erythematosus {chronic autoimmune disease}), these side effects dissipated when

medication was removed; additional side effects include: sedation (3/10) and drooling (4/10);

agranulocytosis and neutropenia were not present in any subject

Conclusion - clozapine is an option for primary psychosis individuals who are not responding to classical

antipsychotics; potential side effects and weekly blood monitoring are a limitation of this

medication, but they should not preclude clozapine use in treating this population; individuals

with primary psychosis may require 100-400mg/day of clozapine for control of psychotic

symptoms; ability to tolerate dosage influenced by speed of drug titration, age, sex, comorbid

illness, and concurrent medications; recommends starting at 6.25-12.5mg doses and titrating

improvement while on clozapine somewhat weak; small sample sizes and retrospective study

limit findings

Intro - clozapine shown effectiveness over classical antipsychotics in treatment of shizophrenic individuals with no, or few, extrapyramidal side effects; potential limitation of this drug in elderly however is potential to cause other side effects including: drowsiness, salivation, tachycardia, dizziness, constipation, nausea, vomiting, agranulocytosis, and hypotension; only studies with clozapine have been done with PD or dementia patients; current study with psychosis

Subjects - 4 patients (3-female, 1-male) with psychosis, 3 with comorbid dementia

-Subject 1 - chronic paranoid schizophrenia with paranoid delusions, auditory/visual hallucinations, aggression, possible DAT, parkinsonism due to neuroleptics; resistant to typical antipsychotics

-Subject 2 - chronic undifferentitated schizophrenia with agitation, aggressiveness, auditory hallucinations, and delusions; psychosis, subcortical dementia, & tardive dyskinesia

-Subject 3 - auditory/visual hallucinations, paranoia, PD, & DAT

-Subject 4 - paranoia, delusions, & auditory/visual hallucinations, mild cognitive impairment

Method - clozapine administered to 4 patients

-Subject 1 - initial dose (25mg) of clozapine caused drooling, muscle rigidity, urine incontinence; subject

transferred to acute unit & given intravenous fluids, all side effects gone by next day; 3 wks

after initial dose clozapine given again at lower dose (12.5mg) cause other meds were not

working, this time there was improvement in psychotic & behavioral symptoms; subject then

on continuous clozapine at 43.75mg/day

-Subject 2 - after initial dose (12.5mg), patient unresponsive, hypotensive, & bradycardic (slow heart rate); transferred to acute unit to stabilize her; side effects gone after 1 day; clozapine never given again

-Subject 3 - initial dose (12.5mg) caused unresponsiveness & bradycardia; taken to acute unit where fluids

improved responsiveness, but heart rate did not increase, so pacemaker put in; following

surgery, 12.5mg clozapine attempted - was improvement in behavior, psychosis,

parkinsonism, and functional ability, no side effects apparent

-Subject 4 - initial dose of 6.25mg/day increased to 37.5mg/day; paranoia, delusions, cognition all

exacerbated by medication; taken off clozapine & mental status and psychotic symptoms

gradually improved; never given clozapine again

Conclusion - all subjects had clozapine-caused side effects, although this statement must be tempered as the

presence of patient-specific factors make the cause/effect relationship between psychosis and

medication and side effects more difficult; combination of effectiveness and side effects; authors

suggest that in individuals with dementia, initial sensitivity to clozapine may exist causing the

resulting side effects; although at least in this study, early sensitivity did not preclude clozapine

users from receiving assistance from the drug in the future once an appropriate dose was found;

overall suggestion that an initial dose of 6.25mg be utilized; even with this lower dose, patients

should be constantly monitored for potential side effects

Criticism - improvement in patients apparently concluded subjectively or at least by clinical judgement; authors put

positive spin on results even though adverse reactions abundant throughout their work

Intro - study focused on use of clozapine in elderly individuals with psychosis who were resistant to treatment to

other antipsychotics

Subjects - 8 individuals at least 65 years old with psychosis unable to be treated by classical antipsychotics

Method - clozapine administered to individuals already taking various benzodiazepines, antidepressants, and

lithium

Results - 6 of 8 showed improvements, other 2 became much more confused than pre-treatment with clozapine;

orthostatis hypotension was a common adverse reaction

Conclusion - authors support use of clozapine in those elderly individuals who are not responding to typical

antidepressants or mood stabilizers and/or are suffering significant side effects from these;

suggested that initial dose of 12.5mg be given at night as long as the patient does not have

significant adverse reactions and then increase the dosage by 6.25-12.5mg every 3 days; the

administration

Intro - this was both a review study of past research and a current study of 6 elderly schizophrenic individuals and

the effectiveness and potential limitations of clozapine use

Subjects - elderly individuals with schizophrenia prescribed clozapine

Method - all subjects given clozapine

Results - review of literature concluded that little empirical research has been done on elderly and the use of

clozapine; overall review of literature found that the effectiveness of clozapine in the elderly was similar

to the younger adult population, however a variety of adverse reactions had a higher incidence in the older

population including: leukopenia, agranulocytosis, postural hypotension, and confusion; 2/6 developed

agranulocytosis

Conclusion - although good effectiveness of clozapine in elderly schizophrenia patients, incidence of

agranulocytosis much greater than once thought; authors suggest that if clozapine is used in

elderly, one should use great caution

Criticism - no mention of dosages used in retrospective studies or suggested for initial use in future studies

Intro - this was a retrospective review of elderly individuals in a hospital for assistance with severe psychosis or

behavioral disruption receiving clozapine

Subjects - 20 individuals with either psychosis or behavioral disruption symptoms

Method - administered clozapine; assessed during hospital stays and then at 2-14 mths follow-ups while still on

clozapine; average daily dose was 210mg/day

Conclusion - authors conclude that clozapine useful in assisting with behavioral disruption, although this

medication likely puts the patient at great risk of developing leukopenia

Criticism - although authors reported average daily dose of clozapine, would have been more helpful if they had

noted the dosage patients averaged when developing particular side effects

Overall, the current risk/benefit analysis of clozapine use in the elderly unfortunately presents quite conflicting results. Of the ten research articles/review chapters, I concluded that six present findings arguing for the use of clozapine in this population, whereas the other four either state that this medication should not be used with the elderly or at least should be used with extreme caution. There seems to be a variety of reasons for the conflicting findings.

Because of the poor findings of this review, a variety of research questions continue to exist. I am still not comfortable with the research on clozapine use in any of the elderly subject pools presented here. Future research must begin to look at more homogenous elderly populations, while also controlling for comorbid illnesses. Likewise, studies need to focus attention on the effect that other common elderly medications have on the effectiveness of clozapine for psychosis. One area of agreement in these studies is that at high levels of clozapine (i.e., 300mg/day), the majority of elderly individuals tend to have very deliberating side effects. However, future research should focus on why such different results are being found at lower dosages. For example, some studies found very beneficial effects at low doses (i.e., 12.5mg/day), whereas others had subjects who responded to similar low doses with extreme adverse reactions. Finally, it would be interesting to look at the potential differences in clozapine effectiveness when looking at variations in both age and gender.

Overall then, because of the nature of conflicting findings, the general conclusion of this review must be tempered. It does seem safe to say that the use of clozapine has a much greater potential for effectiveness for the elderly with psychosis than the classical antipsychotics, particularly with the negative symptoms. Likewise, the incidence of acute extrapyramidal reactions and tardive dyskinesia seems to be much lower. However, as this review presents, clozapine use for psychosis in the elderly does have its limitations. A variety of studies found high incidences of agranulocytosis, hypotension, and sedation. Likewise, as stated above, even at seemingly low doses (i.e., 12.5mg/day) of clozapine, severe adverse reactions (i.e., bradycardia) occurred.