schizophrenia in the elderly

Schizophrenia in the ElderlyGuidelines for Management

Martha Sajatovic,1 Subramoniam Madhusoodanan2 and Peter Buckley1

1 Department of Psychiatry, Case Western Reserve University, Cleveland; and NorthcoastBehavioral Healthcare, Cleveland, Ohio, USA

2 Department of Psychiatry, State University of New York, Health Science Center at Brooklyn, NewYork; and St John’s Episcopal Hospital, Far Rockaway, New York, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031. Prevalence of Schizophrenia in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042. Presentation of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043. Late-Onset Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054. Special Considerations in the Management of Schizophrenia in the Elderly . . . . . . . . . . . . . 105

4.1 Changes in Pharmacokinetics and Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . 1054.2 Medical Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064.3 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064.4 Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

5. Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085.1 Conventional Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085.2 Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

5.2.1 Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095.2.2 Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105.2.3 Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105.2.4 Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115.2.5 Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

5.3 Other Drug Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126. Other Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Abstract The treatment of schizophrenia in older populations poses special challengesfor patients, family members and clinicians. These include changes in manifes-tation of schizophrenic illness in later life, age-related changes in response topharmacological treatments and psychosocial issues associated with older lifestatus.As with younger individuals, antipsychotic medications constitute the main-

stay of treatment for schizophrenia in the elderly. However, the drug treatmentof schizophrenia is substantially affected by the aging process. Medication sen-sitivity is pronounced in the elderly, largely due to age-related changes in thebody’s capacity to metabolise psychotropic and other drugs. Other relevant fac-tors include higher rates of physical comorbidity, drug-drug interactions and age-related adverse effects. Generally, the appropriate starting dose of antipsychotic

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medication in the elderly is 25% of the adult dose. Total daily maintenance dosesmay be 30 to 50% of the adult dose.The use of conventional antipsychotics in the elderly is limited because of

their association with extrapyramidal symptoms and anticholinergic and cardio-vascular adverse effects. The advent of atypical antipsychotics has revolutionisedthe treatment of psychosis in the elderly. Based on the general psychiatric liter-ature, the atypical agents have been found to be as efficacious as conventionalagents in reducing positive symptoms, more efficacious against negative symp-toms, and to have a much more benign adverse effect profile.Nonpharmacological issues in the management of schizophrenia in the elderly

are at least as important as in younger individuals. Older individuals may faceadditional challenges that affect health outcome, such as living alone or beingunable to drive. All drug treatments should be partnered with supportive ap-proaches and psychosocial interventions thatmaximise treatment compliance andimprove outcome.

1. Prevalence of Schizophrenia in the Elderly

The elderly constitute a rapidly growing propor-tion of our population. In the US currently, 1 in 8adults is over the age of 65 years, while by 2030, 1in 5 adults will be over the age of 65 years.[1] It isknown that the elderly utilise a disproportionateamount of healthcare resources. While only appro-ximately 12% of the US population are over the ageof 65 years, this group utilises 31% of all medica-tions prescribed.[2] Given these changing demogra-phics, and the high utilisation of healthcare ser-vices by the elderly, it is imperative that healthcaresystems and individual providers gain increased fa-miliarity and understanding of the health needs ofthe elderly population. This includes the manage-ment of serious mental disorders, such as schizo-phrenia, in older adults.The prevalence of schizophrenia among adults

aged 65 years or older has been estimated to bebetween 0.1% and 1.0%.[3-5] It has been reportedthat 35% of elderly patients treated in public psych-iatric facilities have schizophrenia, and up to 12%of nursing home patients have schizophrenia.[3] Ina recent report on health resource utilisation in astate psychiatric hospital, 68% of hospitalised wo-men age 50 years or over had a diagnosis of schizo-phrenia or schizoaffective disorder.[6]The treatment of schizophrenia in older popula-

tions poses special challenges for patients, family

members and clinicians. These include changes inmanifestation of schizophrenic illness in later life,age-related changes in response to pharmacologi-cal treatments and psychosocial issues associatedwith older life status. In this paper we review guide-lines for the recognition and treatment of schizo-phrenia in the elderly.

2. Presentation of Illness

The life course of schizophrenia into later adult-hood has not been studied sufficiently and is there-fore not clearly understood.[7,8] Opinions on prog-nosis and outcome in schizophrenia have reflectedthe evolution of diagnostic criteria for schizophre-nia and have been influenced by trends in health-care such as deinstitutionalisation.Kraepelin[9] originally used the term ‘dementia

praecox’ to define the severe functional impairmentseen in individuals with schizophrenia on long termfollow-up. For many years, clinicians and resear-chers, particularly in North America, held the strongbelief that schizophrenia was a disorder with onsetonly in young adulthood, and that universally pooroutcome was to be expected.[10] Later investigatorsdescribed a more variable time of onset and a muchmore positive longitudinal outcome. Favourable out-comes (either recovery or greatly improved end-state) were reported in 46 to 68% of patients.[11-17]Ciompi[13] found that only 18% of individuals withschizophrenia had ‘severe’ end-stage illness on lon-

104 Sajatovic et al.

© Adis International Limited. All rights reserved. CNS Drugs 2000 Feb; 13 (2)

gitudinal follow-up. Although not entirely consis-tent, a general finding among later research on out-comes in schizophrenia is that there is some globalsymptom lessening. McGlashan[18] has reported thatthe process of schizophrenia appears to plateau af-ter 5 to 10 years of manifest illness.Others havedemonstrated that although theremay

be apparent overall improvement, there are changesin the types of symptoms manifested by elderlypatients with schizophrenia. It has been suggestedthat overall positive symptoms such as hallucina-tions and delusions tend to diminish over time,[19,20]while negative symptoms have a tendency to wors-en.[8] Male gender may be associated with greaterdeterioration in negative symptoms later in life.[20]It has been hypothesised that there may be a genderdifference in outcomes in late life schizophrenia,with older women having relatively worse outcomescompared with older men.[21] This may be attribut-able to hormonal changes experienced by postmen-opausal women.[22]Although elderly individuals with schizophren-

ia may have impaired global cognitive perform-ance compared with aging individuals without schi-zophrenia, their cognitive impairments do not showthe type and severity of deficits seen in individualswith degenerative neurological disorders such asAlzheimer’s disease.[8,23-25] Cognitive impairmentmay be greater in individuals with more severe ne-gative symptoms.[8,26] It is possible that a decreasein positive symptoms, with concurrent negative sym-ptom worsening, may lead to an under-recognitionand under-treatment of elderly individuals with schi-zophrenia as these individuals may not always re-quire acute care or hospitalisation, and their symp-toms may not be as readily recognised by familyor caregivers.

3. Late-Onset Schizophrenia

DSM-III[27] restricted the diagnosis of schizo-phrenia to individuals with age of onset prior to age45 years. This was changed in DSM-III-R[28] andmaintained in DSM-IV[29] to allow for the inclu-sion of individuals with age of onset at any time inlife.

Harris and Jeste[11] reported that, based upon areview of primarily European literature, approxi-mately 13% of all patients with schizophrenia haveonset of symptoms in the fifth decade, 7% in thesixth decade and 3% thereafter.Late-onset schizophrenia, which has also been

called ‘paraphrenia’, generally follows a chroniccourse similar to early-onset schizophrenia.[30] Theterm paraphrenia has been defined differently byvarious authors and is not found in either DSM-IVor ICD-10.[31] However, positive symptoms suchas hallucinations and persecutory delusions areparticularly common in late-onset schizophrenia.Compared with early-onset schizophrenia, late-onsetschizophrenia is also characterised by fewer nega-tive symptoms, less loosening of associations andless inappropriate affect.[32]Women are at greater risk of developing late-

onset schizophrenia comparedwithmen, particularlyif they are socially isolated and have hearing im-pairments.[33] Jeste et al.[32] have reported that indi-viduals with late-onset schizophrenia may respondwell to lower doses of antipsychotic medicationcompared with individuals with early-onset illness.

4. Special Considerations in theManagement of Schizophrenia in the Elderly

The drug treatment of schizophrenia is substan-tially affected, in terms of response and adverseeffects, by the aging process. Sensitivity to medi-cation is more pronounced in the elderly than inyounger individuals, in large part due to age-relatedchanges in the body’s capacity to metabolise psy-chotropic and other drugs. Other relevant factorsinclude higher rates of physical comorbidity, drug-drug interactions and age-related adverse effects.

4.1 Changes in Pharmacokinetics and Pharmacodynamics

Age-related changes in the metabolism and phy-siology of the gastrointestinal, hepatic, renal andcardiovascular systems substantially alter drug dis-tribution in the elderly.[34,35] These changes are high-lighted in table I. Collectively, these changes may

Schizophrenia in the Elderly 105


result in a greater fraction of active, non–proteinbound drug than would occur if the same dose wasgiven to a younger individual.Age-related changes in liver enzyme levels are

not uniform [i.e. the level of some cytochrome P450(CYP) isozymes decreases while the level of othersis unchanged]. As a result, different drug effectsmay occur depending upon the interactions and CYPsystem involved. An age-related reduction in plas-ma albumin level results in more active drug beingavailable. In addition, since renal clearance decrea-ses with age, the duration that active drug remainsin plasma is prolonged.The proportion of bodyweight which is com-

prised of adipose tissue increases with age. Thismay reduce the total amount of available drug foragents which are lipophilic, as is the case for mostpsychotropic drugs.[34] A decrease in body watercontent may increase concentrations of hydrophillicdrugs such as lithium. Just as age-related changesaffect the metabolism of antipsychotic medications,they also affect the metabolism of other psycho-tropic and nonpsychotropic drugs.[36] Thus, the pro-pensity for drug-drug interactions is heightened be-cause of this overall decline in metabolism withage.There is also recent work examining the pattern

and distribution of central dopamine receptors overthe life course. These data suggest a decrement inreceptors with advancing age.[37]

4.2 Medical Comorbidity

Medical illness in the elderly is common, withan estimated 80% of individuals having at least one

chronic medical disability.[38] A number of inves-tigators have reported that both physical morbidityand mortality are greater in psychiatric patients com-pared with the general population.[38,39]There is a growing appreciation of the extent

and complexity of medical comorbidities in pati-ents with schizophrenia.[40-42] Conditions which areover-represented in patients with schizophrenia in-clude respiratory, cardiovascular, gastrointestinaland neoplastic disorders. The excess of respiratorydisorders may be partly explained by the ubiqui-tous smoking among persons with schizophrenia.[43]The high prevalence of medical comorbidity is alsoconfirmed in postmortem studies of elderly pati-ents with schizophrenia,[44] showing evidence ofarteriosclerosis, plaque formation and cytoplasmicinclusions which are suggestive of comorbid med-ical/neurological illnesses.Greater physical comorbidity, in addition to the

diminished capacity of elderly patients to metabo-lise drugs, is likely to further compromise brainfunction and to predispose patients to neurotoxicityfrom antipsychotic medications.[45] One recent studyof psychotropic polypharmacy in an elderly, institu-tionalised population of patients with chronic schi-zophrenia illustrates this point.[46] Therewas a 33%increase in risk of natural death, predominately fromcardiovascular and respiratory diseases, among el-derly schizophrenic patients in this 10-year pro-spective study. Antipsychotic polypharmacy, malegender, endentulousness (toothlessness) and advan-cing age were among the independent predictors ofheightened risk for mortality in these elderly pa-tients with schizophrenia.

4.3 Adverse Effects

Elderly patients with schizophrenia are particu-larly at risk of the adverse effects of antipsychoticmedications, especially motor adverse effects. It iswell known that the incidence of both extrapyra-midal symptoms (EPS) and tardive dyskinesia (TD)increases with age.[47,48] Hoffman et al.[49] notedantipsychotic-induced parkinsonism in over 60%of elderly patients who were receiving convention-al antipsychotic drugs. Acute EPS, such as dysto-

Table I. Age-related changes affecting the distribution of psy-chotropic drugs in the elderly

Delayed gastric emptying

Reduced levels of plasma proteins, particularly albumin

Reduced circulatory volume

Decreased cerebrovascular perfusion

Decreased synthesis and activity of hepatic microsomal enzymes

Increased relative and absolute amount of adipose tissue

Decreased body water

Decreased renal blood flow

Impaired glomerular filtration and reduced renal drug clearance



nia, occurs in elderly patients at lower doses thanis observed in younger patients with schizophre-nia.Emergence and persistence of TD is amajor risk

in elderly patients.[50-53] Woerner and colleagues[52]reported a 31% incidence of new onset TD amongan elderly population (mean age of 77 years) treatedwith conventional antipyschotics who had been fo-llowed prospectively for 43 weeks. This popula-tion has now been followed for up to 7 years andthe cumulative incidence is over 60%. More re-cently, Jeste et al.[53] examined time to emergenceof TD in an elderly cohort treated with typical anti-psychotics. Among a antipsychotic-naïve subgroup,the cumulative incidence of TD at 1 and 3 monthswas 3.4 and 5.9%, respectively. The overall 1-yearincidence of TD varied from 22.3 to 36.9%, de-pending on the extent of prior exposure to antipsy-chotics among these patients. These data confirmthe high rates of TD in the elderly and suggest thatTD may occur shortly after exposure to conven-tional antipsychotics (almost 6% by 3 months).It has been postulated that the greater propensity

for TD in elderly patients with schizophrenia maybe the result of an interaction between neurodevel-opment and neurodegenerative processes with ad-vancing age and medication response.[54] Identi-fied risk factors for increased risk of TD in theelderly include:• prior exposure to conventional antipsychotic me-dications

• a previous history of alcohol (ethanol) abuse• pre-existing movement disorder• use of conventional antipsychotic medication atdaily doses greater than haloperidol 3 mg/dayor chlorpromazine 150 mg/day.[55]Distinguishing TD from ‘idiopathic’ or ‘senile’

involuntary movements in the elderly can be prob-lematic.[47] One estimate suggested that subtle abnor-mal involuntary movements can be detected (whencarefully assessed for) in about half of the elderlypatients who had ever been exposed to antipsy-chotic medications.[56]Available data for the new antipsychotics show

lower rates of EPS and TD in the elderly than are

seen with conventional agents.[57,58] Moreover, thereis evidence that clozapine may reduce severe TDand tardive dystonia in elderly patients with schiz-ophrenia.[59] On the other hand, these new antipsy-chotics pose different adverse effects which mayaffect elderly patients. For example, some investi-gators have reported that greater age increases therisk of agranulocytosis during clozapine therapy.[60]Although there are currently insufficient data onbodyweight gain during maintenance therapy withthe atypical antipsychotics in elderly patients, thiseffect has been reported in younger cohorts.[61] Thealready high physical comorbidity in older patientgroups suggests that the complications of drug-induced bodyweight gain and the possible subse-quent emergence of type 2 (non–insulin-dependent)diabetes mellitus will be of greater concern than inyounger patients.In a similar manner, high rates of cardiovascular

illness in the elderly may predispose the patients topossible cardiac effects of antipsychotic medica-tions.[62] In addition, postural hypotension from bothtypical and atypical antipsychotics occurs more re-adily in the elderly and is a major reason for thelow and slow titration required for antipsychoticmedications in this patient group. This adverse ef-fect is of particular concern because patients mayfall and injure themselves when high doses of med-ication are used.[63]Excessive sedation is another concern which may

result in a similar unfavourable outcome. Elderlypatients are also more sensitive to the anticholin-ergic adverse effects of antipsychotics. These canbe seen as constipation, delirium, glaucoma andurinary retention, and may be associated with theuse of both typical and atypical antipsychotic med-ications.[64,65]

4.4 Drug-Drug Interactions

The higher rates of polypharmacy due to co-existing physical illness and the diminished cle-arance of drugs make elderly patients with schi-zophrenia particularly susceptible to drug-druginteractions.[34,64,65] Moreover, the situation may



be further complicated by the greater use of over-the-counter preparations in the elderly.[66]Drug-drug interactions may occur at multiple

levels in the metabolic pathway, although the pro-pensity for adverse effects is heightened when drugscompete for degradation through the same CYP sys-tem.[65] This is of particular relevance for the useof combination therapies in the elderly patient. Forexample, even the modest addition of a selectiveserotonin (5-hydroxytryptamine; 5-HT) reuptake in-hibitor (SSRI) may cause up to a 6-fold increasein the plasma concentration of clozapine.[67] Com-monly observed drug interactions which occur dur-ing the treatment of schizophrenia in the elderly arelisted in table II.Since internists may be primary caregivers to

elderly patients with schizophrenia it is essentialthat nonpsychiatric clinicians be familiar with therange and complexity of drug interactions in psy-chiatry. The ready availability of psychiatric drughandbooks which catalogue potential drug interac-tions[68] is helpful.

5. Drug Treatment

As with younger individuals, antipsychotic med-ications constitute the mainstay of treatment forschizophrenia in the elderly. As has been discussedin section 4, age-related pharmacokinetic and phar-macodynamic factors, comorbid medical illnessesand concurrent medications increase the vulnera-bility for adverse effects and drug interactions inthe older population. The geriatric psychopharma-cology maxim ‘start low and go slow’ should befollowed in the use of these medications. Gener-

ally, the appropriate starting dose in the elderly is25% of the adult dose.[69] Total daily maintenancedoses may be 30 to 50% of the adult dose. Somepatients may require higher doses because of ge-netic variability of CYP metabolism. Giving themedications in divided doses, in a slow titration canalleviate some adverse effects such as postural hy-potension and sedation.In spite of generally lower doses in geriatric treat-

ment, it is still important not to under-medicateor discontinue medication too soon. Antipsychoticmedications in the elderly, as with younger indi-viduals, can require 6 weeks or longer for optimumtherapeutic effect.The dose of antipsychotic medication for an older

patient with schizophrenia tends to correlate inver-sely with current age and with age at onset of ill-ness.[55] Dose requirements often decrease over timein chronically ill patients with schizophrenia.[69]

5.1 Conventional Antipsychotics

Most studies of conventional antipsychotics inthe elderly have been conducted in patients withdementia or organic and functional psychosis. Allconventional antipsychotics are equally effective.The selection of a drug depends upon the adverseeffect profile, target symptoms and comorbid med-ical conditions.The use of conventional antipsychotics in the

elderly is limited because of their association withTD, EPS, and anticholinergic and cardiovascularadverse effects. Among the conventional antipsy-chotics, low doses of high-potency drugs, such ashaloperidol and fluphenazine, have a lesser tendency

Table II. Common antipsychotic drug interactions in the elderly

Combination Effect

TCAs and conventional antipsychotics Raises blood antidepressant concentrations

SSRIs and clozapine Raises blood clozapine concentrations

Risperidone and clozapine Raises blood clozapine concentrations

Smoking Lowers blood antipsychotic concentrations

Cimetidine Lowers blood antipsychotic concentrations

Anticonvulsants, antihypertensives, sedatives Additive sedative and confusional effects

Anticholinergic drugs Additive memory and confusional effects

SSRIs = selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors; TCAs = tricyclic antidepressants.



to cause adverse effects such as sedation and pos-tural hypotension comparedwith low-potency drugs,and thus are preferred for elderly patients. Thesedrugs have the additional advantage of being use-ful in noncompliant patients because of the avail-ability of depot preparations.[70] Elderly individu-als with late-onset psychosis have been reported tohave more positive outcomes with long-acting in-jectable antipsychotic medication preparations com-pared with oral formulations.[71] The high-potencydrugs, however, cause more EPS, particularly theacute dystonic reactions.Concomitant anticholinergic medications should

be avoided if possible, as even low doses may beassociated with cognitive impairment in elderly in-dividuals.[72] In patients who are very agitated andexperience insomnia, low doses of thioridazine maybe useful, but its anticholinergic adverse effect po-tential may be a problem in patients with prostatichypertrophy and memory impairment.

5.2 Atypical Antipsychotics

The advent of atypical antipsychotics has rev-olutionised the treatment of psychosis in the el-derly. The general psychiatric literature indicatesthat the atypical agents are as efficacious in reduc-ing positive symptoms as the conventional agents,more efficacious against negative symptoms, andto have a much more benign adverse effect profile.The currently marketed atypical agents are cloz-

apine, risperidone, olanzapine and quetiapine. Thesedrugs are available in the US and UK and a numberof other countries worldwide. Table III illustratesthe receptor binding profiles of atypical antipsych-otics, while table IV illustrates the pharmacokin-etic properties of these agents. Controlled head-to-head studies of these atypical agents in the elderlyare required to determine their comparative effi-cacy and safety; these studies are currently under-way.

5.2.1 ClozapineNo placebo-controlled, randomised studies of

clozapine have been conducted in large samples ofelderly patients with schizophrenia. Howanitz etal.[78] conducted a 12-week double-blind study of

clozapine and chlorpromazine in 42 elderly pati-ents who had schizophrenia and concluded that bothagents were effective treatments for psychosis andbehavioural disturbances. The incidence of adver-se effects, including haematological symptomsand EPS, was similar in the 2 groups. The majorityof other published studies of clozapine in the el-derly include retrospective surveys and case re-ports.[79-84] Their results indicate moderate to goodefficacy and very low rates of EPS, but significantother adverse effects including delirium, somno-lence, orthostasis/falls, agranulocytosis/leucope-nia and cardiac effects.Sajatovic et al.[85] assessed the effectiveness of

clozapine therapy in a sample of 329 older adults(age 55 years and older) in the US Veterans Ad-ministration healthcare system over a period of 5years. Overall, patients improved while receivingclozapine therapy and a particularly good responsewas seen in positive symptoms. Mean dosage was278 mg/day, with generally long titration periods(up to 90 days at some sites). Overall improvementon the Brief Psychiatric Rating Scale (BPRS)[86]items indicating aggression suggest that the highdegree of assaultiveness in this study populationwas reduced by clozapine therapy. There were nosuicides over the 5-year period in this elderly sam-ple, supporting the report byMeltzer andOkayli[87]that clozapine may decrease suicidality. Patientsbetween the ages of 55 and 64 years had a some-what better response to clozapine compared withpatients over the age of 65 years.Alvir et al.[60] report that older age is associated

with an increased risk for agranulocytosis. Womenmay also be at greater risk for leucopenia.[60] Zayasand Grossberg[88] recommended that in elderly pa-tients, clozapine should be used only after 2 trialsof conventional antipsychotics have failed.The advantages of clozapine therapy in the eld-

erly include no apparent incidence of EPS/TD, andefficacy against both positive and negative sympt-oms. Currently, clozapine remains the only anti-psychotic medication with clearly demonstrated ef-ficacy in treatment-refractory schizophrenia.[89] The



recommended starting dosage of clozapine in el-derly patients is 6.25 to 12.5 mg/day.

5.2.2 RisperidoneNo controlled randomised trials of risperidone

with adequate sample sizes have been conducted inelderly patients with schizophrenia. Themany pub-lished reports include case series,[90] and retrospec-tive[91-93] and open-label[94-97] studies. All reportedmoderate to good efficacy. The most frequent ad-verse effects of risperidone were sedation, dose-dependent EPS, dizziness and postural hypotension.Patients who were receiving concurrent SSRIs orvalproic acid (sodium valproate), both of which canincrease serum risperidone concentrations throughCYP2D6 inhibition, appeared to be at a higher riskfor developing EPS.[92,93]In a multicentre prospective open-label 12-week

study,[97] the safety, tolerability and efficacy ofrisperidone were evaluated in 103 elderly patientswith schizophrenia (75%) or schizoaffective disor-der (25%). The patients were assessed at baselineand over the 12-week period. At end-point, symp-tom severity (Positive and Negative Syndrome Scaletotal and subscale scores)[98] and severity of EPSRating Scale scores[99] were significantly reducedfrom baseline. No clinically significant changes inelectrocardiograms, laboratory test results or vitalsigns were noted. The authors concluded that ris-peridone is well tolerated and efficacious in elderlypatients with schizophrenia or schizoaffective dis-order. The mean risperidone dosage at end-pointwas 2.4 ± 1.3 mg/day. In most patients (73%), themean dosage was less than or equal to 3 mg/day.

Some improvement in cognitive functions has beenreported in elderly patients with schizophrenia whowere treated with risperidone.[100]The advantages of risperidone in the elderly in-

clude no or minimal anticholinergic effects and ef-ficacy against both positive and negative sympt-oms. In addition, the drugs is associated with a lowincidence of EPS and TD (at low doses). For exam-ple, in elderly patients with psychosis, the risk ofTD after 9 months of treatment was found to besignificantly lower with risperidone than haloperi-dol.[101]The average dosage of risperidone required for

elderly patients with schizophrenia is about 2 to 3mg/day. This is higher than mean dosage of ap-proximately 1 mg/day prescribed for elderly pa-tients with dementia.[57] The starting dosage ofrisperidone for elderly patients is 0.5mg once ortwice daily.

5.2.3 OlanzapineFew reports on the use of olanzapine in elderly

patients with schizophrenia have been published.In a study of 238 elderly patients with schizo-

phrenia or Alzheimer’s dementia, Satterlee et al.[102]reported that there were no significant differencesin either efficacy or safety between patients receiv-ing olanzapine or placebo. The lack of efficacy wasattributed to an inadequate dosage of olanzapine(1 to 8mg/day). In amore recent study of 59 elderlypatients with psychosis who received 5 to 20 mg/day of olanzapine, the drug was reported to havean excellent efficacy and tolerability profile.[58] Themost frequently reported adverse effects of olan-

Table III. Receptor binding profiles of atypical antipsychotic agents. Symbols indicate the relative affinity of the agents for each receptorsubtype (Ki and IC50 values will vary within the indicated range)[73-76]

Drug Dopamine D1 Dopamine D2 Serotonin5-HT1A

Serotonin5-HT2A

Muscarinic M1 Adrenergic-α1 Histamine H1

Clozapine +++ +++ + ++++ ++++ ++++ ++++Risperidone +++ ++++ ++ ++++ 0 ++++ +++Olanzapine ++++ ++++ + ++++ ++++ ++++ ++++Quetiapine + ++ + +++ + ++++ ++++Ziprasidone +++ ++++ ++++ ++++ 0 ++++ +++++ indicates affinity for receptor, from high (++++) to low (+); 0 indicates no affinity for receptor; IC50 = concentration of drug that inhibits bindingof a radiolabel by 50%; Ki = inhibition constant.



zapine were insomnia, somnolence, headache, hy-pertonia, asthenia and constipation.Olanzapine was also found to be well tolerated

and effective in elderly patients with schizophreniain studies by Madhusoodanan et al.[93,103] and Sa-jatovic et al.[104] In both studies, the mean dailydose of olanzapine was 8 to 10 mg. The primaryadverse effects in these 2 studies were sedation,bodyweight gain, mild anticholinergic effects, andmild dizziness and orthostasis. Bodyweight gainassociated with olanzapine may be of concern, par-ticularly in elderly patients with cardiovascular co-morbidities. In 11 elderly patients with schizophre-nia who received 10 mg/day of olanzapine, meanbodyweight gain was 1.59kg (3.5lb) after a meantreatment duration of 23.5 days.[93] In contrast, inthe report by Sajatovic et al.[104] bodyweight gainover 12 weeks was only approximately 1kg.Preliminary data from studies which included

both younger and older patients with schizophreniado not appear to show any significant cognitivechanges with olanzapine.[104,105]Advantages of olanzapine in the elderly include

a low incidence of EPS and good effect on positiveand negative symptoms. The incidence of TD inelderly patients treated with olanzapine has not beensystematically evaluated, although studies are cur-rently underway. The recommended dosage of ol-anzapine for elderly patients with schizophreniaappears to be in the range of 5 to 10 mg/day.

5.2.4 QuetiapineResults of a 12-week interim analysis of an open-

label 52-week study of quetiapine in elderly pa-tients with psychotic disorders have recently beenpublished.[106] The 151 patients received a meantotal daily dose of quetiapine 100mg. At end-point,significant improvements in symptom severity werereported on the BPRS[86] and Clinical Global Im-pression Scale,[107] and severity of EPS was signif-icantly reduced. The most common adverse eventsof concern were somnolence (32%), dizziness (14%)and postural hypotension (13%). No clinically im-portant changes in results of haematological testsor tests of liver function or mean corrected QT in-terval were noted.Advantages of quetiapine include negligible EPS

and minimal anticholinergic effects, with good ef-fectiveness on positive and negative symptoms.Eventhough the median dosage used in the above studywas 100mg/day, in our clinical experience patientswith schizophrenia often requiremuch higher dailydoses in the order of 300 to 600mg.

5.2.5 ZiprasidoneZiprasidone is a new antipsychotic which is likely

to be marketed in the near future (it is currently atpreregistration phase in the US and is registered inSweden, and phase II studies are ongoing in Ja-pan). Ziprasidone is a potent antagonist of seroto-nin 5-HT2A, 5-HT1A and 5-HT1D receptors. It hashigh affinity for the 5-HT2C receptor as well as beinga potent dopamine D2 receptor antagonist. Zipras-

Table IV. Pharmacokinetic properties of atypical antipsychotics and implications for use in elderly patients[77]

Drug Metabolite t1⁄2 (h) CLR and t1⁄2 changes in theelderly

CYP enzyme involved in metabolism(potential drug interactions)

Clozapine Norclozapine and clozapineN-oxide (very limited activity)

4-12 CLR decreased CYP1A2, CYP2D6, CYP3A4(theophylline, digoxin, warfarin)

Risperidone 9-Hydroxy-risperidone (active) 20a CLR decreased; t1⁄2 prolonged CYP2D6 (inhibitor drugs such asquinidine)

Olanzapine 10-N-glucoranide,N-demethyl-olanzapine (inactive)

30a CLR decreased; t1⁄2 prolonged CYP1A2, CYP2D6b (theophylline,tacrine, fluvoxamine, carbamazepine)

Quetiapine Multiple (main metabolite is asulphoxide; generally inactive)

6a CLR decreased; t1⁄2 prolonged CYP3A4 (phenytoin, thioridazine)

a Mean values.

b Minor route.

CLR = renal clearance; CYP = cytochrome P450; t1⁄2 = elimination half-life.



idone inhibits reuptake of serotonin and noradren-aline (norepinephrine) to a moderate degree.[108]Clinically, ziprasidone appears to be an effec-

tive and well tolerated antipsychotic in younger pa-tients. It is associated with a low incidence of EPSat clinically utilised doses;[109] however, its adverseeffect profile in the elderly is unknown.

5.3 Other Drug Treatments

No systematic studies of other drug treatmentsin elderly patients with schizophrenia have beenconducted. Augmentation strategies for patients withsymptoms that have not responded adequately toantipsychotics include use of benzodiazepines, anti-depressants, lithium, carbamazapine, valproic acid,gabapentin, lamotrigine, reserpine, propanolol, clon-idine, levodopa and electroconvulsive therapy. Com-bination treatments with conventional and atypicalagents and2atypical agentshavebeen attemptedwithsome success in younger patients.[110] Such meth-ods, however, may be associated with increasedadverse effects. Geriatric patients, in view of theirpharmacological vulnerabilities, will have to be veryclosely monitored if such treatments are imple-mented.Insomnia or sleep disturbance may be a signifi-

cant problem in older adults with schizophrenia.With age, most individuals experience more sleepfragmentation/interruption and less sleep time.[37]In general, the optimum treatment of sleep disor-ders associated with schizophrenia in older adultsinvolves treatment of the underlying psychotic con-dition.[69] As the psychotic illness improves, insom-nia and agitation generally improve concurrentlywith other psychiatric symptoms. However, manyclinicians augment antipsychotic medication withsedative/hypnotic medication as symptoms stabi-lise, particularly in cases of acute exacerbation ofillness. Medication which may be utilised includebenzodiazepines, and nonbenzodiazepine hypnoticssuch as zolpidem. The use of shorter-acting benzo-diazepines may avoid problems of accumulationand prolonged toxicity in the elderly, but care shouldbe taken to avoid rebound insomnia or other poten-tial withdrawal symptoms.[37] As noted with other

combination treatments, geriatric patients with schi-zophrenia must be closely monitored for drug-druginteractions and adverse effects when these aug-mentation treatments are used.

6. Other Interventions

Nonpharmacological issues in the managementof elderly patients with schizophrenia are at leastas important as with younger individuals. Older in-dividuals may face additional challenges that affecthealth outcome, such as living alone or being un-able to drive. Issues of poverty, substance abuse,malnutrition and elder abuse may complicate thepresentation and management of schizophrenic ill-ness.[111,112] The continued ‘deinstitutionalisation’of elderly patients, or rather their ‘transitionalisa-tion’ into nursing homes, may exacerbate the dis-continuity in care between mental healthcare andmedical care for this population. It has been shownthat patients with schizophrenia have poor accessto healthcare services, both in terms of the avail-ability of medical resources and the delay in receiv-ing appropriate care.[113] Community outreach andcase management may be particularly beneficial inpreserving care continuity. For elderly individualswith paraphrenia, visits by a community psychiat-ric outreach nurse have been demonstrated to havepositive effects on treatment response.[71] Legal is-sues such as competency and living wills may needto be addressed with appropriate input from health-care providers.For clinicians treating the older individual with

schizophrenia, compliance with medication remainsan issue, as it does with younger individuals. Med-ication noncompliance may manifest as overuse andabuse of medications, forgetting to take medica-tions, and changes in medication dosages or timingof medications.[114] The most important compo-nent contributing to medication noncompliance inolder people is the total number of times per daydrugs must be taken, and the total number of med-ications taken concurrently.[115] Optimum compli-ance is achieved by giving very specific, simple in-structions and asking follow-up questions to ensurethat the patient understands directions.[95]



7. Conclusion

Our understanding of schizophrenia in the el-derly has been somewhat limited in the past. Cur-rent data suggest that illness manifestation in theelderly with schizophrenia differs compared withthat in younger individuals with schizophrenia, asdoes response to treatment. The treatment of olderadults with schizophrenia is made more challeng-ing by age-related biological factors which affectdrug response, the presence of comorbid medicalillness and increased potential for drug-drug inter-actions. The newer antipsychotic medications showgreat promise in improving psychotic symptoms inolder individuals with schizophrenia, while mini-mising adverse effects. All drug treatments shouldbe partnered with supportive approaches and psy-chosocial interventions which maximise treatmentcompliance and improve outcome.

Acknowledgements

The authors are grateful for the support of NorthcoastBehavioral Healthcare System and for the secretarial assis-tance of Mrs Pamela Burton.

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