antipsychotics in older patients

ADVERSE EFFECTS Drugs & Aging 6 (4): 312-323. 1995 117Q-229X/95/0004-<l312/S06.00/0

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Antipsychotics in Older Patients A Safety Perspective

Bruce G. Pollock and Benoit H. Mulsant Departments of Psychiatry and Pharmacology, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, USA

Contents Summary ......................... . 1. Indications for Use of Antipsychotics in Older Patients

1.1 Delirium ... 1.2 Dementia . . . . . . 1.3 Schizophrenia . . . . 1.4 Delusional Disorder . 1.5 Mood Disorders . . .

1.5.1 Psychotic (Delusional) Major Depression . 1.5.2 Bipolar Disorder (Mania) . . . . . . . . . .

2. Special Considerations Regarding Use of Antipsychotics in Older Patients. 2.1 Gerontokinetics.

2.1.1 Absorption . 2.1.2 Distribution . 2.1.3 Metabolism 2.1.4 Excretion ..

2.2 Pharmacodynamics 2.2.1 Cardiovascular Effects 2.2.2 Cognitive Effects ... 2.2.3 Extrapyramidal Effects

3. Conclusions . . . . . . . . . . . . .

· 312 · 313 · 313 · 313 · 314 · 314 · 314 .314 · 315

315 315 315 315

· 316 317 317 317 317 319 320

Summary Age is a major source of variation in drug response. Social, medical and physiological heterogeneity intertwines to complicate geriatric pharmacotherapy. Inappropriate and excessive use of medication may be the most significant treatable health problem in the elderly_

Older people are especially sensitive to antipsychotics, which are disproportionately prescribed to them. Antipsychotic side effects and adverse reactions are intensified and protean in an older population, ranging from disabling to deadly. It is therefore essential that the use of antipsychotics be based on clear indications, guided by knowledge of both age-related and individual determinants of drug clearance and action. Prospective and frequent assessments for adverse effects are also essentiaL

Antipsychotics in Older Patients

1. Indications for Use of Antipsychotics in Older Patients

Many older patients treated with antipsychotics will experience extrapyramidal and anticholinergic effects. Therefore, any discussion of these medications must be balanced by considering their potential benefit within a framework separating theoretical from empirically based rationales (see table I). In the US, the OBRA-87 regulations for nursing homes limit psychotropic drug use to specific indications which require explicit documentation. Before the implementation of these regulations by the US Healthcare Financing Administration, it was estimated that as much as 50% of antipsychotic use in nursing homes would not meet these new standards.[ll Recent data suggest substantial reductions in antipsychotic drug use occurred in the 30 months after the regulations came into forcePl Indications for antipsychotics include hallucinations, delusions and disordered thought and behaviour. The occurrence of these symptoms in late life is indicative of a number of different psychiatric illnesses including delirium, dementia, schizophrenia, and delusional and mood disorders.l31

1.1 Delirium

Frank hallucinations and delusions are present in many delirious patients, often resulting in the prescription of an antipsychotic.l41 Because of its minimal anticholinergic and hypotensive properties, haloperidol is usually considered the antipsychotic of choice in the treatment of agitated delirium in the elderly.l5,61 In intensive care units (ICU), high dosages (e.g. 40 to 100 mg/day) have been administered intravenously, alone or combined with other drugs.l7,81 These rapid tranquillisation protocols are better avoided in older delirious patients. Oral or intramuscular administration of low doses of haloperidol (e.g. 0.5 to Img 2 to 3 times daily) alone is recommended,ESl In the ICU, low dosages of haloperidol can also be given intravenously to older patients who are unable to take medications orally and for whom multiple intramuscular injections are undesirable (because of


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Table I. Biological and clinical evidence supporting the use of antipsychotics in the treatment of psychoses occurring in late life

Biological Clinical Clinical evidence evidence in evidence in

patients of patients aged mixed ages >60 years

Delirium 0 C D

Dementia 0 D A

Early-onset ++++ A B schizophrenia

Late-onset +t NA D schizophrenia

Delusional disorder + C D

Psychotic major +t B D depression

Bipolar disorder + B D (mania)

Abbreviations and symbols: A = replicated controlled, double-blind trials; B = unreplicated controlled, double-blind trial(s); C = naturalistic prospective trial(s), large case series; D = small case series, case reports, clinical experience; NA = not applicable; 0, +, +t, +++, ++++ = absent to very strong biological evidence implicating dysregulation of dopaminergic system.

bruising, bleeding, and elevations in creatinine phosphokinase levels ).l4-61

1.2 Dementia

The prevalence of delusions and hallucinations among patients with degenerative dementia is estimated to be around 30%.[91 In the context of dementia, psychotic symptoms have been associated with excess disability, increased caregiver burden, aggressiveness and premature institutionalisation.[IO,iil However, only a few methodologically sound studies have assessed the treatment of psychosis in demented patients. Even these well designed studies have not distinguished improvement due to nonspecific decrease in agitation from specific amelioration of delusions or hallucinations.li2-i61 On the basis of the available data, several reviews[9, i71 and I meta-analysis[i81 have concluded that antipsychotics yield, at best, a modest improvement, in up to one-half of demented patients with agitation, whereas many of these patients fail to improve or actually deteriorate. Other psychotropic medications and placebo have been reported to produce similar improvement.[l9-211

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Thus, when attempting to treat behavioural disturbances in a demented patient with an antipsychotic medication, physicians should identify clear target symptoms and should discontinue medication after 4 to 6 weeks if clinically relevant improvement is not obtained. In patients who fail to tolerate or who do not respond to antipsychotics, alternative drug classes should be consideredJ22)

1 .3 Schizophrenia

Most older schizophrenic patients experienced onset of their disease earlier in life.l23) However, very little is known about the aging of schizophrenic patients. Thus, the treatment of schizophrenia in late life is extrapolated from treatment of younger patients. The selection of a specific antipsychotic remains based on the side effect profile of the drug. Given the sensitivity of older patients to both anticholinergic and extrapyramidal adverse effects (see section 2.2.3), intermediate potency antipsychotics such as perphenazine, loxapine or molindone are preferred. For some older patients, depot antipsychotics may be necessary to insure compliance. [24)

The use of anticholinergic medications should be avoided or minimised since even at low dosages they are associated with cognitive impairment in the elderly.[25) Some of the newer antipsychotics, which have a relative lack of extrapyramidal effects, may have a special role in late life.[26) Case series have reported the use of clozapine in older patients at dosages of 12.5 to 400 mg/day (with most patients receiving 50 to 150 mg/day).I27) This drug may be particularly useful for the treatment of psychosis occurring in the context of Parkinson's disease.l28,29) Elderly patients may, however, be at higher risk for specific adverse effects of clozapine such as agranulocytosis,[30) hypotension[27,3l) or deliriumJ29.32)

No report on the use of risperidone in older patients has yet been published. Before the prescription of newer antipsychotics to older schizophrenic patients can be recommended, clinical studies need to be conducted in this population.

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Pollock & Mulsant

During the past decade, schizophrenia of late onset (i.e. after age 45 years) has been the subject of renewed interest. [33) Typically, late-onset schizophrenia has been characterised by a high female to male ratio, premorbid personality with schizoid or paranoid traits, hearing and visual loss, paranoid symptomatology, absence of formal thought disorder or negative symptoms and a tendency towards chronicity. Some noncontrolled data support the use of traditional antipsychotics in the treatment of late-onset schizophrenia. Overall, more than 125 patients have been reported to respond moderately well to various anti psychotics at dosages typically around 200 mg/day chlorpromazine equivalents, or about half the necessary (threshold) dosage reported in young schizophrenic patients.[26,34-36)

1 .4 Delusional Disorder

Delusional disorder considered as a discrete disorder is a rare condition with a prevalence estimated at 20 to 30/100 000. The peak age of onset is between 25 and 45 years)37,38) Somatic subtypes may be more prevalent in older people)39) Although pimozide has been reported to produce symptomatic relief in almost two-thirds of treated patients,[39) its relative effectiveness has not been tested in any controlled study. With careful clinical monitoring for its cardiac and extrapyramidal adverse effects ,[40) low-dose pimozide (0.5 to 2 mg/day) may be prescribed to older patients presenting with delusional disorder. Alternatively, a medium potency antipsychotic can be tried (e.g. perphenazine 4 to 12 mg/day).

1.5 Mood Disorders

1.5.1 Psychotic (Delusional) Major Depression A quarter to one-half of elderly patients admit

ted to hospital for major depression present with delusions or hallucinationsJ41) The treatment of psychotic major depression in late life is currently based on the results of trials involving younger patients or patients of a variety of ages. In these patients close to 20 trials have demonstrated the low effectiveness (i.e. less than 40% response) oftricy-



clic antidepressants alone.l42] In younger patients, the addition to a tricyclic of an antipsychotic at a high dosage (i.e. above 400 mg/day chlorpromazine equivalents) significantly increases the rate of response.l43-45] In an ongoing study,[46] we have found that most elderly patients with psychotic major depression can tolerate a combination of nortriptyline plus perphenazine at about half the antipsychotic dosage used in younger patients (i.e. 12 to 24 mg/day). However, the effectiveness of such a combination remains to be determined.

Amoxapine is an atypical heterocyclic derived from loxapine that possesses both antidepressant and antipsychotic properties. It can induce extrapyramidal symptoms and tardive dyskinesia.l47] In patients with psychotic major depression (mean age: 45 ± 12 years), amoxapine 400 mg/day was found to be as effective as a combination of amitriptyline 200 mg/day plus perphenazine 32 mg/day.l48] Extrapyramidal adverse effects were less prevalent with amoxapine, while other adverse effects were comparable in both groups. Despite this potential advantage, the lack of supporting data precludes unequivocally recommending amoxapine for late life psychotic major depression.

1.5.2 Bipolar Disorder (Mania) Psychotic features, in particular grandiose delu

sions, commonly occur during manic episodes of bipolar or schizoaffective disorders.[49] A significant proportion of bipolar patients experience their first manic episode late in life and older age of onset has been associated with a higher prevalence of psychotic symptoms.[50,51]

Lithium in the elderly may carry additional risks of neurotoxicity and hypothyroidism. Core manic symptoms (i.e. elevation of mood, grandiose ideas, increase in activity, distractibility and impaired judgement) have been treated with both sedating and non sedating antipsychotics.[52] It is possible that newer antipsychotic agents, such as risperidone, may have the most suitable therapeutic index for the treatment of psychosis associated with bipolar disorder in late life. Systematic trials are urgently needed.

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2. Special Considerations Regarding Use of Antipsychotics in Older Patients

2.1 Gerontokinetics

Most pharmacokinetic differences seemingly associated with age are related to conditions that, although more frequent in the elderly, can occur in patients of all ages. Such differences include diminished renal or cardiac function, concurrent illnesses and drug treatment. For instance, elderly patients are far more likely to experience adverse drug-drug interactions: in the community the average older American is taking 3 prescription medications; this increases to an average of 9 drugs in nursing home residents.l53-55]

2. 1. 1 Absorption With age, there are decreases in stomach acid

and in the size of the gastric absorbing surface as well as reductions in mesenteric blood flow. Antipsychotics, however, are absorbed by passive diffusion, and so the rate and extent of absorption is not significantly altered. Clinicians should, however, be alert to the extensive use of compounds with huge absorbing surfaces (e.g. Metamucil® and Maalox®) or medications with anticholinergic properties which can interfere with the rate of gastrointestinal absorption.

2. 1.2 Distribution Important changes in distribution occur with

age. The percentage of body fat relative to lean body mass and total body water increases with age. Between the ages of 20 and 75 years, total body water decreases 15 to 20%, extracellular fluid decreases 35 to 40%, and the fraction of bodyweight as fat increases 25 to 45%.154] For lipid-soluble drugs, such as anti psychotics that distribute in body fat, the volume of distribution is increased, resulting in an increase in the half-life. Half-life is directly proportional to volume of distribution divided by clearance; thus, even if there is no change in clearance, an increase in volume of distribution will lead to a prolonged half-life.

Albumin levels may diminish with age-associated illness, while <XI-acid glycoprotein levels increase.


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This will differentially affect the protein binding of acidic and basic drugs, respectively. The antipsychotics are bound with greater affinity to <Xl-acid glycoprotein, an acute phase reactant protein, which increases markedly in patients with arthritis and cancer. The extent of protein binding will affect the absolute concentration of free drug and the volume of distribution. Nonetheless, it is now appreciated that any increase in free drug will be buffered by redistribution and elimination, maintaining the free fraction of drug and diminishing the effect of plasma protein displacement.[S6]

2.7.3 Metabolism

Data obtained in senescent rodents supported the conventional view that there is an age-associated decline in phase 1 drug-metabolising enzyme activity (hydroxylation, demethylation). There is now evidence ranging from hepatic samples to drug metabolic phenotyping that suggests there is not a uniform age-associated decline in liver metabolism by the cytochrome P450 isozymes.[S7,S8] There has also been an increased appreciation of the diversity ofP450 isozymes. CYP2D6 (debrisoquine hydroxylase) is the isozyme responsible for hydroxylation of many psychotropics. In older patients not receiving medication, CYP2D6 does not appear to undergo an age-associated decline.[S7] Demethylation, mediated by other isozymes, such as CYP2C19, CYP1A2 or CYP3A4, may be more subject to age-associated impairment as has been shown for tricyclic antidepressants.l59,60]

Hepatic blood flow is decreased by 40% in people older than 65 years compared with those under 25. For highly metabolised drugs, a reduction in hepatic first-pass effect is to be expected. Higher plasma concentration to dose ratios have been observed in older patients for thioridazine, thiothixene and perphenazine.l6l -63] It should be appreciated, however, that information on potentially interacting medications, in these studies, was not given. In a rare pharmacokinetic study of elderly psychiatric patients, plasma concentrations of thioridazine, mesoridazine and sulforidazine were 1.5 to 2 times higher than in younger patients.l64] In a larger study of haloperidol, however, the plasma

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Pollock & Mulsant

concentration to dose ratio was not found to be increased in older patients,[6S] nor was there an increase in the ratio of fluphenazine according to a recent report.l66]

Age-related changes in body composition and reductions in hepatic volume and blood flow also emphasise individual differences in drug metabolism, a major factor in the variability of drug concentrations in older patients.

Five to 10% of the population lack CYP2D6.[67] In addition, many drugs competitively or noncompetitively inhibit this enzyme. The list of drugs definitively shown to be metabolised by CYP2D6 continues to grow and includes perphenazine, thioridazine and risperidone.l68-70] For haloperidol, only the oxidation of reduced haloperidol back to haloperidol appears to be directly mediated by CYP2D6PI] Nonetheless, poor CYP2D6 metabolisers demonstrate higher plasma concentrations of haloperidol and its active reduced metabolite compared with extensive CYP2D6 metabolisers.l72]

There are emerging data associating the poor debrisoquine metaboliser phenotype with an increased incidence of adverse effects from antipsychotic drugs, both retrospectively and prospectivelyP3,74]

Antipsychotics are themselves moderately potent inhibitors of CYP2D6. This has been specifically confirmed in vivo for haloperidol, perphenazine and thioridazinePS-77] The results of studies utilising in vitro microsomal systems suggest that thioridazine, perphenazine and haloperidol are somewhat more potent inhibitors of CYP2D6 than is chlorpromazine.[78,79] The potential of antipsychotics to inhibit drug metabolism would suggest a need for particular caution in elderly patients taking other CYP2D6 substrates, such as tricyclic or serotonin-reuptake inhibitor antidepressants, ~blockers, dextromethorphan, some antiarrhythmics and anticancer drugs.[46,80] Moreover, the conversion of codeine to active morphine also depends on CYP2D6. Codeine has, in fact, been shown to be an ineffective analgesic when CYP2D6 is inhibited by quinidine.l81 ]



2. 1.4 Excretion The decrease of creatinine clearance with age is

well established.l57] This decrease affects the elimination of the hydroxylated metabolites of antipsychotics. This has not, as yet, been systematically studied in older individuals. In younger schizophrenic patients, increased levels of the reduced metabolite of haloperidol has been associated with a less favourable outcome.l82] Thus, active hydroxylated metabolites of some antipsychotics, such as reduced haloperidol, the sulfoxide metabolites of thioridazine, 7 -hydroxyperphenazine and 9-hydroxy-risperidone, may affect therapeutics to a greater degree in the elderly.

2.2 Pharmacodynamics

Pharmacodynamics refers to the relationship between the effect of a drug and its measurable concentration. In older patients there is a general reduction in homeostatic mechanisms (e.g. postural control, orthostatic circulatory responses, thermoregulation, visceral muscle function and higher cognitive function). This may interfere with the ability to adapt to changes in the environment and may be manifest as an adverse drug reaction. For instance, antipsychotics increase the risk of falls and hip fracture in the elderly.[83.84] Similarly, older patients may be at higher risk for subtle disturbance of hypothalamic thermoregulatory mechanisms associated with antipsychotics.l85] An overview of the adverse effects associated with antipsychotics is presented in table II. Cardiovascular and central nervous system (CNS) effects are of particular concern in the elderly and are discussed in more detail below (see sections 2.2.1 and 2.2.2).

2.2. 1 Cardiovascular Effects Specific age-associated changes have been

most extensively investigated for autonomic receptor-mediated effects.[86] Reductions in ex2- (but not ex 1-) adrenoceptor responsiveness may occur with age, and could contribute to the increased risk of orthostatic hypotension in elderly patients, a cardiovascular effect of major concern in this age group. The use of lower potency drugs should be

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avoided because they are more likely to cause orthostatic hypotension. Tachycardia is an additional concern with the use of lower potency medications, secondary to their anticholinergic effects. Pimozide and thioridazine, at routine clinical dosages, may cause electrocardiographic changes consistent with delayed ventricular conduction.

Diphenylbutylpiperidines, such as pimozide and fluspirilene, are potent calcium channel blockers.l87] Although thioridazine is less potent in this regard, it is used clinically at relatively high concentrations. Accordingly, it has also been shown to be capable of calcium channel antagonism in the clinical setting. [88]

In addition, all antipsychotics possess membrane-stabilising (quinidine-like) properties that may delay cardiac conduction. Electrocardiographic changes have been noted most frequently for the diphenylbutylpiperidines and piperidines (e.g. thioridazine and mesoridazine) and least often for the piperazines (e.g. perphenazine and trifluoperazine).l89] In patients with pre-existing conduction disturbance there is a clear need for increased watchfulness.

Haloperidol, when used in high parenteral doses, may cause delays in ventricular conduction, associated with the lethal torsade de pointes arrhythmiaPO] The risk of antipsychotic-cardiovascular drug interactions is considerably amplified since many of these medications interact both metabolically and dynamically. For example, quinidine and diltiazem will inhibit not only cardiac conduction, but CYP2D6 as well. In older patients, treated long term with antipsychotics, the prevalence of obesity, poor nutritional status and increased triglyceride levels may contribute to additional cardiovascular risk.[91]

2.2.2 Cognitive Effects Studies of the cognitive effects of antipsychotic

medication are beset by methodological difficulties and are virtually nonexistent in the elderlyJ92] Diminished cholinergic functioning in the CNS of older patients and, in particular, those with Alzheimer's disease, may render them more sensitive to the central anticholinergic effects of antipsy-


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Table II. Adverse effects associated with antipsychotic medications

Adverse effects

Peripheral anticholinergic effects

Dry mouth

Blurred vision

Constipation

Urinary hesitancy/retention

Central anticholinergic effects

Confusion - delirium

Cardiovascular effects

Postural hypotension

Tachycardia

Electrocardiographic changes

Extrapyramidal effects

Dystonic reactions

torticollis

oculogyric crisis

opisthotonos

Parkinsonism

masked facies, rigidity

motor retardation, akinesia

resting tremor

shuffling gait

drooling

Akathisia

Withdrawal and tardive dyskinesias

Other adverse effects Sedation

Bodyweight gain

Neuroleptic malignant syndrome

Allergic reactions, hypersensitivity

Leucopenia, agranulocytosis

Sexual and endocrine effects

Seizures

Risk

+

+

+

+

+

+

+

+

Effect

L

L

L

H

L

H

L

L

L

Pollock & Mulsant

Comment

May progress to impaction and ileus

May present as urinary tract infection or overflow incontinence

Patients with Alzheimer's disease are at particularly high risk

Associated with falls and fractures

Cardiac arrhythmias in overdose; caution with pimozide, thioridazine and intravenous haloperidol

Clozapine does not cause these adverse effects

May present as Pisa syndrome in the elderly

Avoid anticholinergic medications in elderly patients

May be mistaken for depression

Associated with falls and fractures

May be mistaken for psychotic agitation

Onset may occur after only brief use (a few months) in the elderly

Give antipsychotics as one daily dose at bedtime

Akin to malignant hyperthermia

Rare cases of jaundice associated with phenothiazines; skin rash; photosensitivity

Very rare (1/5000) except with clozapine

Delayed or retrograde ejaculation; impotence; breast enlargement and tenderness

Rare except with clozapine

Abbreviations and symbols: H = effect more common with high·potency anti psychotics; L = effect more common with low-potency antipsychotics; + = elderly patients may be at higher risk; - = elderly patients may be at lower risk.

chotic medication.l931 These effects can range from blurred vision and cognitive impairment to frank delirium, which may occur at therapeutic concentrations.[94,951 The increased anticholinergic effects of low-potency antipsychotics clearly limits their use in an older population.

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Oversedation is also associated with low potency antipsychotics because of histamine (HI) antagonism. It can lead to confusion and disorientation and contribute to urinary incontinence, pneumonia, decubiti, poor eating and aspiration. In addition to cognitive blunting, apathy and akinesia,



antipsychotics may directly cause depression.!96] Although short term antipsychotic treatment has been associated with decreased attention and vigilance in young patients with schizophrenia, long term treatment improved performance on tests of sustained attention and visual-motor functions.!97) There are, as yet, no systematic studies in older patients, but clinical experience raises concerns for those who are already intellectually compromised. Moreover, Alzheimer's patients with delusions have been noted to have greater cognitive impairment and a more rapidly progressive dementia. Whether this is entirely the consequence of neuropathological changes, or the result of increased use of antipsychotics in these patients, remains an important question.[98,99]

2.2.3 Extrapyramidal Effects Reductions in nigrostriatal dopamine levels

predispose the elderly to antipsychotic-induced parkinsonism. This adverse effect is dependent on the potency, dose and duration of antipsychotic treatment and can persist for up to 36 weeks following medication discontinuation.!IOo,I01) Manifested by worsening gait and posture, and bradyand hypokinesia, antipsychotic-induced parkinsonism may occur in 75% of patients.l102) Of particular concern in the frail elderly, drug-induced parkinsonism has been associated with a clinically significant decline in activities of daily living.l101 ,102) There has been increased attention given to pre-existing neurological signs in Alzheimer's disease. Extrapyramidal signs are common in this illness, particularly as it progresses.1103-105) Patients with Lewy body dementia have recently been recognised as being exquisitely sensitive to the extrapyramidal effects of antipsychotics.l 106) Unfortunately, there is not yet a reliable way to identify this condition before a trial of medication.

Acute Dystonia and Akathisia Acute dystonic reactions are less frequent in

older patients and it is speculated that, paradoxically, a hyperdopaminergic state is causative.lI07) Nonetheless, a variant of dystonia, the Pisa syndrome, in which the trunk is flexed and slightly

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319

rotated, has been reported to have a prevalence of 8% in psychogeriatric patients.l108) Unlike the more typical dystonia, which has a rapid onset, Pisa syndrome may appear after several weeks of treatment and may be associated with abnormalities of brain computed tomography,l109)

Akathisia is a particularly tormenting adverse effect which in extreme cases has been linked to suicidality and violence.[1IO) It is more common in older patients treated with higher potency antipsychotics. If objectively assessed for, akathisia may be observed in approximately 20% of elderly patients receiving antipsychotics,l111) Akathisia is frequently unrecognised or misinterpreted as a worsening of psychotic agitation, resulting in increased antipsychotic doses. Akathisia should also be distinguished from restlessness that is not subjectively distressing. The latter is probably a variant of tardive dyskinesia.l 112)

Tardive Dyskinesia Tardive dyskinesia constitutes a severe social

handicap for patients and may impair speech, eating, breathing and gait. Until recently the increased incidence of tardive dyskinesia in the elderly was believed to be due to increased exposure. Two prospective studies have now demonstrated that, regardless of diagnosis, there is a very high onset of tardive dyskinesia in older patients taking relatively low dosages of antipsychotics (Le. :S;100 mg/day chlorpromazine equivalents) for relatively brief periods (cumulative incidence reported as 26 to 45% over 1 year and 31 % after 43 weeks))26,113)

A recent report from Japan suggests that respiratory dyskinesia, a potentially life-threatening complication manifested by an irregular respiratory rate, tachypnoea and grunting, may often be overlooked in older patients.!114) Four risk factors have been identified as increasing the risk of tardive dyskinesia in older patients: prior exposure to antipsychotics, a past history of alcohol (ethanol) abuse, pre-existing movement disorder and the use of antipsychotic daily doses greater than haloperido13mg, or 150mg chlorpromazine equivalents,l26) These investigators have also noted that concurrent smoking and use of anticholinergics may increase


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the severity of tardive dyskinesia. In addition, diabetes has recently been identified as a potent risk factor in 2 carefully conducted case-control studies, where age, gender, dose and duration of antipsychotic treatment were controlled.l Il51

While antipsychotic medications have been discontinued without adverse behavioural consequences in some demented nursing home patients,D161 a controlled trial of targeted antipsychotic use in elderly schizophrenic patients resulted in a greater frequency of psychotic relapse compared with those on maintenance medication.l1171 It should also be noted that those older than age 60 years compared with younger patients are significantly less likely to have remission of tardive dyskinesia upon medication discontinuation.l Il81

Concern with neurological damage caused by oxidative free radicals is a recurring theme.l Il91 Antipsychotics have been implicated in increasing dopamine turnover, leading to increased hydrogen peroxide production, as well as inhibiting mitochondrial complex 1 enzymes and nitric oxide synthase.l120-l221 There is specific concern about haloperidol since its pyridinium metabolite bears a resemblance to I-methyl-4-phenyl-l,2,3,6,-tetrahydropyridine (MPTP), which is capable of destroying dopaminergic neurons to produce parkinsonism.l123,1241 Given the more limited dopaminergic reserve in the elderly, this putative neurotoxicity should be of particular concern when assessing the risk/benefit ratio of antipsychotic treatment.[1 251 The potential benefit of antioxidant treatment [e.g. tocopherol (vitamin E)] remains unproven.

3. Conclusions

The elderly are more likely to be sensitive to drug effects and more liable to experience adverse drug interactions, especially since they are more likely to be taking multiple medications. Before prescribing an antipsychotic to an older patient, it is imperative to obtain a complete record of all medications, which should be kept to a minimum. Assume impaired capacity to metabolise and/or excrete newly initiated medications, but also do not


Pollock & Mulsant

undertreat on the basis of chronological age alone. In general, use mid-potency drugs (e.g. perphenazine) in minimal, efficacious doses, and be vigilant for adverse effects.

Acknowledgements

Preparation of this review and the authors' research described herein were supported by USPHS Grants K07 MH-1040 and MH-49786 from the National Institute of Mental Health.

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Correspondence and reprints: Dr Bruce G. Pollock, Departments of Psychiatry and Pharmacology, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA.


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