cognitive impairment in late life schizophrenia: a suitable case for treatment?

COGNITIVE IMPAIRMENT IN LATE LIFESCHIZOPHRENIA: A SUITABLE CASE

FOR TREATMENT?ROBERT HOWARD*

Section of Old Age Psychiatry, Institute of Psychiatry, London, UK

SUMMARY

The benign side-e�ect pro®les of the atypical antipsychotic drugs have earned them an important niche in oldage psychiatry. Evidence for a speci®c improvement in cognitive function associated with the use of these drugsis inconsistent and the de®nitive studies are still awaited. If these drugs can improve cognitive function in elderlypatients with schizophrenia and schizophrenia-like psychosis, then in terms of patient-years of e�ective treatment ofcognition, this action may be more signi®cant than the treatment of Alzheimer's disease with cholinergic therapies.# 1998 John Wiley & Sons, Ltd.

Int. J. Geriat. Psychiatry, 13: 400±404, 1998.

KEY WORDSÐschizophrenia; cognitive function; clozapine; risperidone

The use of atypical antipsychotic drugs has beenadvocated in the elderly largely on the grounds thatthey are associated with fewer adverse motor e�ects(Jeste et al., 1996). They have also been shown to bee�ective in the treatment of negative symptomsand, as will be examined below, may improvecognitive function in young and elderly patients.Cognitive improvement observed with a change intreatment to an atypical agent in a patient withschizophrenia could be attributable to severalfactors. Alleviation of positive symptoms ofpsychosis which might impair attention orcooperation, negative symptoms which themselvesshow overlap with features of dementia and thee�ects of previously prescribed conventionalneuroleptic drugs may be signi®cant as well as adirect bene®cial drug e�ect upon the cognitivesymptoms of schizophrenia. Psychiatrists respon-sible for the care of elderly individuals withschizophrenia will recognize two distinct groupsof such patients: those with an onset in early adultlife who have `graduated' into old age (Campbell,1997) and those whose illness began in late life.

Graduates, often particularly handicapped bynegative symptoms and unwanted motor e�ectsof conventional antipsychotics, might be expectedto bene®t most cognitively from the newer drugs.In late onset schizophrenia, while negative symp-toms are not prominent (Howard et al., 1993;Almeida et al., 1995a; Jeste et al., 1995) and socialand cognitive impairment are subtle, such patientsare exquisitely sensitive to the development ofdrug-induced Parkinsonism and tardive dyskinesia(Jeste et al., 1993). Improvement in cognitivefunction in this late onset group could be mostconvincingly ascribed to a direct and speci®c druge�ect on schizophrenic cognition.

COGNITIVE DEFICITS INTRINSIC TOSCHIZOPHRENIA

The neuropsychology of schizophrenia is charac-terized by a generalized cognitive impairment,particularly a�ecting the domains of memory andexecutive functioning. Episodic and semanticmemory are disproportionately impaired (Tamlynet al., 1992; McKay et al., 1996), with relativepreservation of implicit memory and procedurallearning (Goldberg et al., 1993a). Poor perform-ance on tests of executive functions is ubiquitous

CCC 0885±6230/98/060400±05$17.50 Received 4 November 1997# 1998 John Wiley & Sons, Ltd. Accepted 28 January 1998

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 13: 400±404 (1998)

*Correspondence to: Dr R. Howard, Section of Old AgePsychiatry, Institute of Psychiatry, DeCrespigny Park, LondonSE5 8AF, UK. Fax: 0171 701 0167. e-mail: [email protected]

(Liddle and Morris, 1991) and is associated withimportant practical outcome measures such ascommunity functioning, social problem-solvingand skill acquisition (Green, 1996). Cross-sectionaland follow-up studies of geriatric chronic schizo-phrenic patients have demonstrated that cognitiveimpairments and negative symptoms are relatedand overlapping, but discriminable, features of theillness (Davidson et al., 1995; Harvey et al., 1996).Patients with onset of a schizophrenia-like illness inlate life do not have prominent negative symptoms(Howard et al.,1993; Almeida et al., 1995a; Jesteet al., 1995), but even the most cognitively intactare impaired, particularly in executive functions(Almeida et al.,1995b; Jeste et al., 1995).

COGNITIVE EFFECTS OF CONVENTIONALANTIPSYCHOTICS

The negative e�ects of neuroleptics on cognitivefunction are seen mainly in tasks which involvevigilance, attention and motor skills (Mortimer,1997). Such e�ects are most prominent followingacute drug administration, and after prolongedprescription are restricted to motor skill impair-ment. Bene®cial e�ects on sustained attention andvisuomotor tasks may be seen after prolongedadministration (King, 1990; Cassens et al., 1990;Stip, 1996). The speci®c e�ect of neuroleptics onmemory function in schizophrenia is unclear andcomplicated by the e�ects of concomitant antic-holinergic therapy (Tune et al., 1982; Cleghornet al., 1990).

ATYPICAL ANTIPSYCHOTICS

Clozapine is a dibenzodiazepine with a�nity forthe D2-family, alpha1, alpha2, 5-HT2, 5-HT1a and1c, histaminic and both nicotinic and muscariniccholinergic receptors (Coward, 1992). While pro-blematic in use because of its broad side-e�ectpro®le, clozapine does o�er a 30±60% responseadvantage in treatment-resistant schizophrenia(Kane et al., 1988; Breier et al., 1993; Tamminga,1997) and is useful in patients with tardivedyskinesia (Tamminga et al., 1994). Risperidonehas a�nity for the D2-family, 5HT2 and alpha1receptors (Borison et al., 1992). If used within therecommended dose range, risperidone has lowmotor side-e�ects; however, motor problems do

emerge in patients requiring higher doses forantipsychotic e�ect. Some authors (eg Jeste et al.,1996) have recommended that initial doses ofrisperidone should be as low as 0.25 mg per dayand that maximum doses in the elderly should notexceed 3 mg per day. Olanzapine is a thienobenzo-diazepine which neurochemically antagonisesdopamine, serotonin, alpha1 and muscarinicreceptors (Bymaster et al., 1996). Therapeuticdoses can be initiated immediately, which isadvantageous for a rapid onset of antipsychoticaction, and the drug produces almost none of themotor or cardiac side-e�ects associated withconventional neuroleptics (Beasley et al., 1996).Sertindole is a phenylindol derivative with nano-molar a�nity to D2, 5-HT2a and 2c and alpha1receptors (Sanchez et al., 1991). E�ective againstpositive and negative schizophrenic symptoms, thedrug has few motor side-e�ects (Zimbro� et al.,1997) but has potential for prolonging the QTinterval and, although use of the drug has not beenassociated with arrythmia, it is probably sensible toavoid its use in patients with heart disease.Quetiapine is a dibenzothiazepine whose bindingcharacteristics parallel those of clozapine except fora lack of muscarinic cholinergic a�nity. E�ectiveagainst both positive and negative symptoms, thisdrug also has a low incidence of motor side-e�ects(Borison et al., 1996; Hirsch et al., 1996).

COGNITIVE EFFECTS OF ATYPICALS INYOUNG PATIENTS

Although only one blind controlled trial compar-ing clozapine with typical antipsychotics has beenpublished (Buchanan et al., 1994), in several studiesof groups of mostly young acute schizophrenicpatients clozapine has been shown to improveperformance on tests of motor function and speed(Classen and Laux, 1988; Hagger et al., 1993),attention (Hagger et al., 1993), stroop interference(Classen and Laux, 1988; Buchanan et al., 1994),the Wisconsin Card Sort Test (Fujii et al., 1997),verbal ¯uency (Hagger et al., 1993; Buchanan et al.,1994) and memory (Meltzer, 1992; Hagger et al.,1993; Buchanan et al., 1994), as well as globalMMSE (Manschrek et al., 1994) and Full Scale IQ(Fujii et al., 1997) scores. Some studies havereported unchanged cognitive abilities withclozapine and the drug has also been shown toimpair performance on logical memory and visual

# 1998 John Wiley & Sons, Ltd. INT. J. GERIAT. PSYCHIATRY, VOL. 13: 400±404 (1998)

TREATING COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA 401

reproduction subtests of the Wechsler MemoryScale and the Wisconsin Card Sort Test (Goldberget al., 1993b) and tests of attention and executivefunction such as trail making (Buchanan et al.,1994). Failure to establish an association betweenimprovements in neuropsychological test perform-ance and changes in symptom levels in these studies(Goldberg et al., 1993b; Hagger et al., 1993;Buchanan et al., 1994) supports the relativeindependence of cognitive impairment and positiveand negative symptoms. Similarly, cognitive im-provement cannot be attributed to the e�ects ofdiscontinuing typical neuroleptics alone (Fujiiet al., 1997) and appears to be sustained for atleast a year (Buchanan et al., 1994; Fujii et al.,1997).

There are fewer published studies of the cogni-tive e�ects of risperidone in schizophrenia. In openuncontrolled trials the drug has been shown toimprove measures of alertness and selective atten-tion (Stip and Lussier, 1996) and working memoryassessed by the Wisconsin Card Sort Test and digitsymbol substitution subtest of the WAIS (Rossiet al., 1997). In both of these studies, the authorsdemonstrated correlations between improvementsin negative symptomatology and cognition.

EVIDENCE FOR COGNITIVE EFFECTS INELDERLY SCHIZOPHRENIA PATIENTS

Although no double-blind studies have beenpublished in peer-reviewed journals, evidencefrom open trials of risperidone treatment of elderlyschizophrenic patients suggests that the drug mayimprove their cognition. In an open-label study of10 behaviourally disturbed chronic schizophrenicswhose mean age was 71, Berman et al. (1996)carried out neuropsychological assessments beforeand during treatment with risperidone. Baselineassessments were made while patients received theirconventional antipsychotic medication, which wasthen stopped and a titrated (to a daily maximumof 6 mg) dose of risperidone given. Patients werereassessed after a least 1 week on risperidone andshowed signi®cant improvements in MMSE score(mean pre-treatment 22.4 and post-treatment 25.5),Digit Symbol Test, word recall and constructionalpraxis. Although the authors conceded that scoreson the ®rst assessment might have been deleter-iously a�ected by conventional neuroleptics andthat practice e�ects might have helped performance

on risperidone, they were able to demonstrate thatthe increase in MMSE score did not correlate withimprovement in psychotic symptoms. In a double-blind comparison of the cognitive e�ects ofrisperidone and haloperidol in 20 elderly schizo-phrenics (mean age 67.4) carried out by the sameauthors (quoted by Jeste et al., 1996), thosepatients who received risperidone had signi®cantimprovement on MMSE score and the BostonNaming Test. Jeste and colleagues (1996) havethemselves investigated the cognitive e�ects ofrisperidone treatment in middle-aged and elderlypsychotic patients with an open uncontrolledstudy. Treatment was with low does of risperidone,on average 2.1 mg per day, over a mean treatmentperiod of 10.6 weeks. In a group of 19 patients(13 with schizophrenia), mean MMSE scoreincreased from 24.2 to 28.2.

CONCLUSIONS

The present quality of evidential data to support animprovement in cognitive function in elderlyschizophrenic patients treated with atypicals isinsu�cient to be convincing, and controlleddouble-blind trials in both graduate and lateonset patients are needed before this e�ect can beruled in or out. The results of such trials will haveimportant implications for patients. Since cognitiveimpairment in schizophrenia appears to be chronicand stable, bene®cial treatments are likely to bee�ective for years or even decades rather than theapparent short-term bene®ts of licensed cognition-improving drugs in Alzheimer's disease. Mean-while, the atypical antipsychotics are most likely tobe prescribed for elderly patients because of thebenign motor side-e�ect pro®le rather than for anybene®cial action on psychotic symptoms. Untildepot preparations of the atypicals are available, itis di�cult to see how they could replace conven-tional drugs in the treatment of isolated paranoidpatients living in their own homes (Howard andLevy, 1992).

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cognitive impairment in late life schizophrenia: a suitable case for treatment?

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