Jay Anderson

                                                                                    Fall, 1998

Background/Reason for Literature Review

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.

Although phenothiazines have had some clinical success in working with psychosis, drug companies throughout the past decade have been searching for new antipsychotics that have similar pharmacological effects, yet diminish the potential for the development of acute extrapyramidal reactions and tardive dyskinesia. These newly developed medications are referred to as second generation antipsychotics. One such new generation antipsychotic is clozapine (Clozaril). Clozapine has been utilized with a variety of diagnoses in the elderly including: acute and chronic psychosis, agitation and aggression as seen in dementia, and delirium. With a high affinity to bind to a variety of receptors, including dopamine, serotonin, acetylcholine, and histamine, clozapine appears to have solid clinical effectiveness in alleviating not just the positive symptoms of psychosis, but also the negative symptoms. Likewise, it does not seem to induce the acute extrapyramidal side effects and tardive dyskinesia in elderly patients to the extent that the classic antipsychotics do. Because of this supposed effectiveness, clozapine, along with other second generation antipsychotics like risperidone, would seem to be the drug of choice for treating psychosis in the elderly. This statement must be tempered, however, as recent studies have found that clozapine may not be the wonder drug it was once thought to be. Clozapine does reduce the risk of extrapyramidal side effects and tardive dyskinesia, but the likely increased risk of agranulocytosis, a blood disorder involving the lowering of white blood cells which then increases one=s risk of obtaining bacterial infections, temper the perception of clozapine as being a wonder drug for elderly psychosis.

The current literature review, utilizing ten recent research articles/review chapters on clozapine, will be a risk/benefit analysis of this medication. The potential benefits of clozapine are widespread, including the treatment of both positive and negative symptoms in psychosis, the reduced risk of extrapyramidal side effects and tardive dyskinesia, and the seemingly higher compliance with medication use as opposed to the classical antipsychotics. The risks associated with clozapine use in the elderly, such as an increased risk of agranulocytosis, seem to temper the excitement of clozapine=s benefits.

Thorpe, L. (1997). The treatment of psychotic disorders in late life. Canadian Journal of Psychiatry, 42 (Suppl 1), 19S-27S.

This review article focused its attention on the practical usefulness of neuroleptic medications in the elderly. Even though the author proceeds to present a variety of research articles that have studied clozapine use in a geriatric population, Thorpe does state that most of the second generation antipsychotics Ahave not been evaluated extensively in elderly populations.@ In support of clozapine=s usefulness over traditional antipsychotics, this review discusses the potential treatment effectiveness of this medication with the negative symptoms of psychosis and also the reduced risk of inducing tardive dyskinesia.

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


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



Wagner, M.L.., Defilippi, J.L., Menza, M.A., and Sage, J.I. (1996). Clozapine for the treatment of psychosis in Parkinson=s Disease: Chart review of 49 patients. The Journal of Neuropsychiatry and Clinical Neurosciences, 8 (3), 276-280.

Intro - Clozapine reported well-tolerated and effective in the treatment of psychosis in Parkinson=s patients; long-

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

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

Method - retrospective study utilizing chart reviews; individuals with psychosis before onset of PD excluded; psychosis (hallucinations, delusions, or both) measured by physicians= impressions on 0-3 (0-gone; 1-improved; 2-no change; 3-worse) scale; clozapine dose; LD (levodopa) dose; and adverse reactions assessed at 3, 6, 12, & 18 months; mean dose of clozapine was 16mg at beginning of study, 24mg at 3 mths, 29mg at 6 mths, 39mg at 12 mths, & 31mg at 18 mths

Results - at 3 months, 76% of 49 subjects had improvements in psychotic symptoms, 70% at 6 mths, 84% at 12 mths, & 70% at 18 mths; overall 92% responded beneficially to clozapine at some point in therapy; 3 of 49 had complete relief of psychotic symptoms; 2 had no relief at all

-side effects were as follows: 6 had some type of effect (1 each had back pain, delirium, drug-induced fever, sedation, and low platelet count; 2 had leukopenia)

-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, J. (1996). Geriatric psychopharmacology. In L.L. Carstensen, B.A. Edelstein, & L. Dornbrand (Eds.), The practical handbook of clinical gerontology (pp. 481-542). Thousand Oaks, CA: Sage Publications, Inc.

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.

6. Lack of research done with elderly. Only subject group with an adequate amount of research completed with clozapine use is Parkinson=s patients.


Shulman, R.W., Singh, A., & Shulman, K.I. (1997). Treatment of elderly institutionalized bipolar patients with clozapine. Psychopharmacology Bulletin, 33 (1), 113-118.

Intro - clozapine=s lower rate of induced extrapyramidal side effects likely result of reduced dopamine-2 receptor

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

(when one=s platelets are extremely low); these all improved at lower doses, this improved

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

Criticism - even though this study=s results are intriguing, one=s excitement must be tempered due to the extremely

small sample size


Musser, W.S., & Akil, M. (1996). Clozapine as a treatment for psychosis in Parkinson=s Disease: A review. Journal of Neuropsychiatry, 8 (1), 1-9.

This review article discusses the clinical usefulness of clozapine treatment for psychosis in Parkinson=s Disease. Classic antipsychotics tend to exasperate the motor symptoms that present in PD. On the other hand, clozapine seems to be much more clinically effective in the treatment of psychosis in PD, particularly refraining from aggravating motor symptoms and may even assist in decreasing the level of these symptoms. Musser and Akil present that clozapine=s ability to treat PD psychosis without exacerbating the motor symptoms is likely a consequence of clozapine only affecting the nesocortical and mesolimbic portion of the dopaminergic system, while avoiding the nigrostriatal portions. The authors proceeded to review the following research articles that support the utility of clozapine in treating drug-induced psychosis in PD:

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

The rest of the studies reviewed were presented in table format. The majority had extremely small sample sizes with obviously limits each=s statistical power and overall generalizability. Likewise, improvement, defined as elimination of psychotic symptoms, lack of exacerbating of psychosis, or improvement in motor symptoms, was usually measured by clinical judgement. With the lack of objective quantitative rating scales, the overall positive effectiveness of clozapine in this population must be tempered. With these limitations in mind, all of these studies reported improvement in at least some of their sample with the following side effects occurring: 11 of 16 studies reported sedation, hypotension reported in 5, agranulocytosis in 1, anticholinergic effects in 6, & confusion in 4.

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.

Sajatovic, M., Jaskiw, G., Konicki, P.E., Jurjus, G., Kwon, K., & Ramirez, L.F. (1997). Outcome of clozapine therapy for elderly patients with refractory primary psychosis. International Journal of Geriatric Psychiatry, 12 (5), 553-558.

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

Results - 7 of 10 subjects= psychosis improved while on clozapine, other 3 taken off clozapine because of lack of

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

Criticism - authors= presentation of pre and post BPRS is not reported in full which makes their statement of

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

limit findings


Pitner, J.K., Mintzer, J.E., Pennypacker, L.C., & Jackson, C.W. (1995). Efficacy and adverse effects of clozapine in four elderly psychotic patients. Journal of Clinical Psychiatry, 56 (5), 180-185.

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


Frankenburg, F.R., & Kalunian, D. (1994). Clozapine in the elderly. Journal of Geriatric Psychiatry and Neurology, 7 (2), 129-132.

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


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

clozapine user=s mental state and blood pressure should be watched closely during the



Herst, L., & Powell, G. (1997). Is clozapine safe in the elderly? Australian and New Zealand Journal of Psychiatry, 31 (3), 411-417.

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


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


Salzman, C., Vaccaro, B., Lieff, J., & Weiner, A. (1995). Clozapine in older patients with psychosis

and behavioral disruption. American Journal of Geriatric Psychiatry, 3 (1), 26-33.

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

Results - all 20 individuals= disruptive behavior decreased, psychoses showed modest improvement; common adverse reaction was sedation; clozapine use was discontinued in 2 patients as respiratory symptoms were induced; seizures occurred in 1 patient; during the post-hospital stay while still receiving clozapine 3 of 20 individuals developed leukopenia

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 Assessment of the Research Related to Clozapine Use in the Elderly

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.

First and foremost, the availability of research in this area is extremely small. In doing this review, I set out to do a risk/benefit analysis with clozapine and one particular section of the elderly population. However, because of the scarcity of research in this area, I was forced to utilize clozapine studies looking at a variety of elderly individuals, including those diagnosed with dementia, bipolar disorder, and schizophrenia among others. Obviously, the heterogeneity of individuals with these diagnoses can be large and limit the cohesiveness of the resulting findings. Heterogeneity of human response to mediation in general is another reason for this review=s conflicting findings. Individual response to clozapine includes not only variation in the therapeutic dose for each individual, but also how each responds to clozapine initially. This latter point was discussed in one of the present studies, as these authors found many of their subjects to respond quite unfavorably initially to clozapine, but upon a second trial, to receive very beneficial therapeutic usefulness. As stated, the elderly individual=s main presenting problem is a conflicting variable, but so too, is these individuals= comorbid illnesses. Some of the current studies did use subjects with similar main presenting problems (i.e., schizophrenia), but found quite different results with the use of clozapine. It seems quite likely that much of this conflicting research was a result of these authors neglecting to control for comorbid illnesses in their subjects. An additional reason for these conflicting findings in this review relates to the speed of titration used in each study. Unfortunately, the majority of these studies did not report specifically their titration rates for each of their subjects. This would have been very useful data as it would allow comparison between titration of studies. Even in the absence of this data, I assume that these authors have a large variation in their rate of titration, which may likely effect their subjects= effectiveness received from clozapine and the resulting side effects. A final problem in this research area, which definitely plays a role in the conflicting findings presented here, are the extremely small sample sizes of the majority of these studies. I realize that initially in a new topic area smaller samples are easier to study, but until large, full-scale samples of homogenous elderly populations are utilized in clozapine research, the error of measurement in this area will continue to be large, as the statistical power of each study is so small.

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.

Even though my conclusion of this review has been more negative than positive to this point, I would recommend the use of the clozapine in the elderly. The potential benefits to decreasing psychosis seem to outweigh the potential side effects that can result. If it is decided to be utilized, an extremely low dosage, 6.25mg/day, should be given at first with the patient being very closely monitored for any adverse reactions. If no side effects occur at this dosage level, titration could occur until each individual=s most effective dosage (i.e., most therapeutic for psychosis, yet least incidence of side effects) is found. Obviously however, because of the scarcity of research in this area, physicians prescribing clozapine in their elderly subjects must use extreme caution as the heterogeneity of individuals= responses to this medication seems quite large.