TREATMENT OF DEPRESSION IN THE ELDERLY:EFFECT OF PHYSICAL ILLNESS ON RESPONSE

MAVIS EVANS1*, MARGARET HAMMOND

2, KEN WILSON

3, MICHAEL LYE

4AND JOHN COPELAND

5

1Consultant Old Age Psychiatry, Wirral Community Healthcare NHS Trust, Liverpool, UK2Research Associate, University of Liverpool, Liverpool, UK

3Professor Old Age Psychiatry, Wirral Community Healthcare NHS Trust, University of Liverpool, Liverpool, UK4Professor Geriatric Medicine, University of Liverpool, Liverpool, UK

5Professor Psychiatry, University of Liverpool, Liverpool, UK

SUMMARY

Objectives. To determine the response to treatment of di�erent subgroups within a sample of physically ill elderlydepressed patients.

Design. Acute geriatric medical inpatients with depression, randomly assigned to an 8-week double-blind placebo-controlled trial of ¯uoxetine.

Main outcome measure. Response rate as de®ned by the 17-item Hamilton Depression Rating Scale.Results. Data were analysed in subgroups according to diagnosed physical problems and concomitant medication.

A logistic regression analysis was performed to identify subgroups valid for separate analysis. Those reaching at least5 weeks of treatment showed a signi®cant improvement compared with the placebo group if they had serious life-threatening disease, cerebrovascular disease, were not demented, or were either on no analgesics or on analgesicsstronger than paracetamol.

Conclusion. While the response to treatment in these subgroups was encouraging, general physicians must not be ledto believe that the answer to depression lies only in pharmacological intervention, just as the belief that the risk±bene®t ratio of such treatment where indicated is too high must be discouraged. # 1997 John Wiley & Sons, Ltd.

Int. J. Geriat. Psychiatry, 12, 1189±1194, 1997.No. of Figures: 0. No. of Tables: 1. No. of References: 27.

KEY WORDSÐold age; depression; physical illness; liaison psychiatry; ¯uoxetine; treatment

Little is known of the prognosis of psychiatricdisorders identi®ed in hospitalized physically illpatients (Mayou et al., 1988). Hawton (1981)found that psychiatric disturbance often persisted,especially in patients with a previous history ofpsychiatric disorder. Feldman et al. (1987) inter-viewed patients after discharge and found thatonly two-thirds were improved psychiatrically at4 months follow-up. Mayou et al. (1988), reportingthe same study, found that those with an a�ectivedisorder on admission continued to make greaterdemands on medical, social and psychiatricservices than matched controls and had double

the mortality rate (although this did not reachsigni®cance).

Several studies have suggested that medically illdepressed patients respond poorly to antidepres-sant treatment (Popkin et al., 1985; Baldwin andJolley, 1986; Meats et al., 1991), although that isnot the experience of others (Evans, 1993; Evansand Lye, 1992; Lakshmanan et al., 1986; Gregoryet al., 1992). Popkin et al. (1985) retrospectivelyreviewed case notes and suggested that pharma-cotherapy may not be the answer to depressiveillness emerging secondary to physical problemsand that `the clinician confronted with depressivesyndromes in the physically ill should considerforms of intervention other than tricyclic anti-depressants'. However, the antidepressants usedin this study were ®rst generation tricyclics:imipramine (most responders), amitriptyline anddesipramine (most side-e�ects), nortriptyline ordoxepin. Newer antidepressants, especially the

* Correspondence to: Mavis Evans, Director of Elderly MentalHealth, Wirral and West Cheshire Community NHS Trust,Clatterbridge Site, Bebington, Wirral L63 4JY, UK.

Contract grant sponsor: Lilly Industries.Contract grant number: BIY BP HC55.

CCC 0885±6230/97/121189±06$17.50 Received 7 May 1997# 1997 John Wiley & Sons, Ltd. Accepted 27 August 1997

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 12: 1189±1194 (1997)

5-HT reuptake inhibitors, are becoming the drugsof choice in the physically ill depressed patientbecause of their lack of anticholinergic side-e�ects,reduced cardiotoxicity and much diminished like-lihood of inducing confusion. Popkin's paper maybest be viewed as an invitation to prescribe, whenappropriate, the less toxic antidepressants nowavailable, rather than as an excuse for therapeuticnihilism in this di�cult group of patients.

A 12-month open prospective study (Evans,1993) of geriatric medical inpatients showed asigni®cant response (p < 0.03) to treatment ofthose with concomitant depression with ¯uoxetineversus no treatment. The mortality rate in thedepressed group was nearly 50% at 1 year,compared with 35% in those psychologically well.The majority of deaths in the depressed groupoccurred in the ®rst 3 months of the study, mostbefore the depression had responded to treatment.The death rate in this group returned to that of theprospectively followed up psychologically wellgroup for the ®nal 9 months of the study,suggesting that the depressive illness had a directe�ect on the mortality rate.

Akiskal and colleagues (1981) reported thatdepression was likely to have a poor prognosis,either becoming recurrent or chronic, when accom-panied by a non-a�ective disorder whether psy-chiatric or medical. Koenig et al. (1992) screenedand followed up consecutive acute geriatric medicaladmissions to a veterans hospital and demon-strated that major depression diagnosed in thesepatients did not resolve once the patient lefthospital, over 60% persisting without improve-ment. Less than 45% of these patients had receivedantidepressants at all, 20% had been givenbenzodiazepines and less than 25% had beentreated for more than 1 week. The `considerableamount' of therapeutic nihilism found was con-sidered by the author to be due to worries over therisk±bene®t ratio of known therapiesÐin thestudy reported he refers to tricyclic antidepressantsand monoamine oxidase inhibitors only. He con-cluded that an e�ective treatment for depression inelderly patients needs to be found, with widespreadeducation of geriatricians in the diagnosis andtreatment of depression.

Gregory et al. (1992) suggest that explanationsfor the apparent association of medical illnesswith poor treatment outcome might include: (1)age as a confounding factorÐmost of the trials oftreatment in the physically ill are in elderly patients;(2) medically ill patients may be given inadequate

doses of antidepressants because of problems withside-e�ects or overcautious physicians; (3) di�erentsubtypes of depression exist, some medication-responsive, some not.

To determine whether the response to treatmentof the physically ill depressed elderly is relatedto their physical pathology and/or treatment,data from a double-blind placebo-controlled trial(Evans et al., 1997) were analysed in subgroupsaccording to diagnosed physical problems andconcomitant medication.

METHOD

Patients aged 65 years and over admitted to theacute geriatric or general medical wards at theRoyal Liverpool University Hospital were eligiblefor the initial project, which was a double-blind,randomized parallel-group study. Subjects receivedeither placebo or ¯uoxetine 20 mg in the morningsfor a target period of 8 weeks. The primarydependent variable was depression measured usingthe 17-item Hamilton Depression Rating Scale(HAMD) (Hamilton, 1960), with a good responsede®ned as reduction in score of 50% and/or a ®nalscore of 10 or less.

Physical history was extracted from all availablemedical case notes, with physical examination,results of laboratory tests or other investigationsand concomitant medication also recorded.Physical illnesses were rated as mild, moderate orsevere, acute or chronic (Burvill, 1990). Ratingswere done on entry to the study by one author(ME), relapse or new illness was recorded as itoccurred as an adverse event by another (MH).

Subjects were seen at weeks 1, 3, 5 and 8 afterentry into the study. Depressive symptoms wereevaluated and scored using the HAMD. Pulse andblood pressure, concomitant medication and con-tact with medical professionals were also recordedtogether with details of any adverse events.

E�cacy analyses were carried out on thosecompleting 3 or 5 weeks of treatment. A logisticregression analysis was performed to identifysubgroups reaching at least a trend (p < 0.10) inthe interactions, and thus which groups would bevalid for separate analysis. Further analysis of thesubgroups used Fishers exact test as sample sizewas small. All tests were two-tailed.

Data from patients reaching at least 3 weeksof treatment were entered into the e�cacy analysis,and then subgroup analyses were performed

INT. J. GERIAT. PSYCHIATRY, VOL. 12: 1189±1194 (1997) # 1997 John Wiley & Sons, Ltd.

1190 M. EVANS ET AL.

according to diagnosed physical problems andconcomitantmedication. Themain subgroup, thosewith a serious physical illness de®ned as cardiac orrespiratory disease rated moderate or severe, ordiagnosis of neoplasm known to the patient, isdiscussed elsewhere (Evans et al., 1997). Furtheranalysis of disease by system involvement wasperformed, looking at respiratory, cardiac, boneand joint problems and cerebrovascular disease.Level of cognitive impairment was also considered,using MMSE score of 23 or less as indicative ofimpairment in this age group (Folstein et al., 1975).

Analyses were then carried out based on the typesof medication each patient was receiving as thismeant the illness was at least severe enough towarrant treatment. Inhalers used were broncho-dilators or steroids for the treatment of chronicobstructive airways disease (COAD). Cardiac medi-cation was de®ned as digoxin, loop diuretics, ACEinhibitors and/or nitrates. The majority of patientswere taking analgesics such as paracetamol, withsome also using mild opiates such as coproxamol ordihydrocodeine. Painful conditions warrantingchronic treatment varied from recurrent headachesor arthritis to abdominal pains.

RESULTS

82 subjects entered the study, 20 men and62 women, mean age 80.4 years (SD 6.6); 51 com-pleted ®ve weeks of treatment and 42 the full eight

weeks of the study. Exclusion criteria and reasonsfor withdrawl have been reported elsewhere (Evanset al., 1997). E�ect of treatment on the groups as awhole did not reach signi®cance, although at eightweeks nearly twice as many patients in the¯uoxetine group had responded to treatment,compared with the placebo group (67% vs 38%).

From the data of those reaching at least 5 weeksof treatment, the subgroups showing a trend inthe interaction of the regression analysis were:serious physical illness, cerebrovascular disease,MMSE < 24, and those patients using paraceta-mol. Analysing data from those reaching at least3 weeks of treatment (i.e. larger numbers), a trendin the interaction was also seen in those patientsusing inhalers and those using night sedation.

No trend was seen in those groups with cardiacdisease, respiratory disease or neoplasm whenanalysed separately, nor in those using cardiacmedication or laxatives. The group using pain-killers stronger than paracetamol was analyseddespite a trend not being shown on logisticregression, as the authors wished to see if anti-depressants showed any e�ect in this group withmore severe pain.Results of the subgroup analysis can be seen in

Table 1.

DISCUSSION

It is important that depressive illness is treatedwhen appropriate as it is well established that

Table 1. Percentage response and number of subjects in each subgroup

Interaction N Fluoxetine Placebo

At least 5 weeks of treatment (N � 51)

Serious physical illness p � 0.065 37 62.5 23.8 p � 0.0233*

No serious physical illness 14 62.5 83.3 p � 0.58

Cerebrovascular disease p � 0.065 19 87.5 27.3 p � 0.0198*

No cerebrovascular disease 32 50.0 43.8 p � 1.00

MMSE > 23 p � 0.033 21 70.0 9.1 p � 0.0075*

MMSE 4 23 30 57.1 56.3 p � 1.00

Rx paracetamol p � 0.098 33 52.9 43.8 p � 0.73

Not Rxd paracetamol 18 85.7 27.3 p � 0.050*

Rx analgesics stronger than paracetamol p � 0.18 25 75.0 30.8 p � 0.0472*

Not rxd analgesics stronger than paracetamol 26 50.0 42.9 p � 1.00

At least 3 weeks of treatment (N � 62)

Rx inhalers (3 weeks � ) p � 0.074 20 63.6 11.1 p � 0.028*

Not Rxd inhalers 42 50.0 45.8 p � 1.00

Rx night sedation (3 weeks � ) p � 0.056 16 83.3 20.0 p � 0.035*

Not Rxd night sedation 46 47.8 43.5 p � 1.00

* Statistically signi®cant.

# 1997 John Wiley & Sons, Ltd. INT. J. GERIAT. PSYCHIATRY, VOL. 12: 1189±1194 (1997)

TREATMENT OF DEPRESSION: RESPONSE OF PHYSICALLY ILL PATIENTS 1191

depression increases morbidity and mortality in theelderly (Baldwin and Jolley, 1986; Evans et al.,1991; Mayou et al., 1988; Murphy, 1983). It is,however, of equal importance that ine�ective orunnecessary treatment is not given, both because ofthe risk of drug interactions or adverse reactionsand also because of the ®nancial cost.The group of patients entered into this study

were heterogeneous, with di�ering physical prob-lems. Recruitment of such a group was consideredvalid as this is the reality of clinical practice. Ourresults have shown that there are subgroups withinthis population with di�ering response to treat-ment, or perhaps with di�erent types of depressiveillness, which present similar signs and symptoms.The depression diagnosed on entry to the studyshould not be seen as reactive to admission as boththe screening process and diagnostic criteria forentry to this trial referred to mental state in theprevious 4 weeks.

All illnesses except the very trivial involve anelement of psychological adjustment. Seriousphysical illness is likely to be a potent psychologicalstressor a�ecting body image, self-esteem, sense ofidentity, capacity to live independently and tomaintain social and family relationships (Rodinand Voshart, 1986). Three-quarters of the patientsin our study met the criteria for life-threateningillness and showed a signi®cant di�erence inresponse to active or placebo treatment. Con-versely, the smaller group with less severe physicalproblems showed no di�erence in treatmentresponse and were perhaps su�ering from seniledysphoria as described by Baldwin and Jolley(1986), where the mood disorder appears to beprecipitated by chronic physical illness, and is notresponsive to pharmacotherapy but does respondto psychosocial intervention.

Cerebrovascular disease was de®ned as thosepatients with diagnosed transient ischaemic attacksand/or stroke, either currently or in the past. Aslong ago as 1962, Kay reported that arterioscleroticbrain disease may play a role in precipitatingdepression in approximately 10% of cases of lateonset a�ective disorder. Magni et al. (1985) showedby regression analysis of their sample of 178 acutemedical inpatients that CNS disease and depressionwere linked. However, the mechanism for thislinkage is not clear. After a stroke, physicaldisability and social handicap can be understoodas mediating factors; site of lesion and amount ofbrain involved may be important, but currentknowledge is contradictory. Robinson et al.

(1983) have postulated destruction of speci®ccatecholamine pathways as an aetiological factor.In the subgroup discussed in this article, ischaemicdamage of at least a subclinical level is likely tohave been occurring in the majority, althoughthe site and extent of damage are not known.Damage to catecholamine pathways may explainthe signi®cant response to ¯uoxetine (p < 0.02), amedication which would potentiate the serotoninavailable.

Analysis of the subgroup by cognitive levelfound those who were cognitively intact (N � 21)showed a highly signi®cant response to activemedication (p � 0.008) whereas those with cogni-tive impairment (N � 30) did not.

Brain damage with cognitive loss probablyimpairs the coping ability of the personality andmay also damage those areas or pathways in thebrain that encourage natural amine production.Follow-up treatment during this trial included thedevelopment of a close supportive relationshipwith the researcher and this was considered to havebeen a factor in producing the placebo responserate in the whole group of 38%. Supportivetherapy probably works through emotionallymediated responses, which may be impaired bythe hopelessness of depression felt by those withintact cognition. Supportive relationships can beseen to be important in those with cognitiveimpairment; perceived or real lack of these mayperhaps be a factor in the high incidence ofdepression found in residential care (Evans et al.,1995; Ames, 1990).

Respiratory disease likely to produce dyspnoea isuncomfortable and frightening. It enforces limita-tions to physical activity, and when severe can leadto feelings of impending death. In their communitystudy, Evans et al. (1991) found a direct relation-ship between the severity of the dyspnoea and thepresence of depressive illness. In the present study,the group diagnosed with respiratory disease didnot show di�erences in interaction to warrant beinganalysed as a separate subgroup, but when thoseactually on treatment for these problems (perhapsan indication of subjective severity) were analysed,a signi®cant di�erence in response to treatment wasshown.

The relationship of depression to pain is com-plex. Pain is a subjective experience; it can varywithin the same person depending on time andcircumstances. Elderly patients, often with somesocial and perceptual isolation and inward focusfor their thoughts and perceptions, frequently

INT. J. GERIAT. PSYCHIATRY, VOL. 12: 1189±1194 (1997) # 1997 John Wiley & Sons, Ltd.

1192 M. EVANS ET AL.

su�er from chronic pain. Depression a�ects painawareness. A depressed chronically sick patient isoften intolerant of pain which is accepted withoutcomplaint when the mood is elevated. It can there-fore be suggested that the need for analgesia in theelderly with chronic conditions may be linked tothe development of a depressive illness needingtreatment. Alternatively, it is well known in painclinics that addition of antidepressants in sub-therapeutic doses to analgesics can help in cases ofintractable pain. Various mechanisms have beendescribed for this action, from increasing serotoninavailability (Stimmel and Escobar, 1986) to theinhibition of encephalin degradation (Hendler,1984). Improvement with active treatment wasnot seen in the group taking paracetamol, perhapsbecause many elderly patients take paracetamol forvarious reasons other than analgesia, for instanceas night sedation.

Depression has been found in 20±50% of acutecardiac patients and 70% or more of these willremain depressed 3 months later (Stern et al.,1976; Schleifer et al., 1989). In our sample over70% were receiving cardiac medication of somekind, but regression analysis using this subgroupdid not warrant its inclusion as a separate group.This can be understood by the fact that myo-cardial infarction, mild congestive cardiac failureor peripheral vascular disease were all classi®ed as`cardiovascular'. Separate diagnoses had beenrecorded for each patient, together with anestimate of severity of mild, moderate or severe,but the numbers of patients with each individualdiagnosis were too few to make individual analysespossible.

This study has shown a positive response to thetreatment of depression by medication in thepresence of serious physical illness or cerebrovas-cular disease. It has also shown the importance of asupportive relationship in the resolution of depres-sion in those with mild to moderate cognitiveimpairment. General physicians must not be led tobelieve that the answer to depressive illness lies inpharmacological intervention; equally to be dis-couraged is the belief that the risk±bene®t ratio ofsuch treatment where indicated is too high. Thepharmacological treatment given, ¯uoxetine 20 mgmane, was well tolerated by all patients in the trial(Evans et al., 1997), and showed a very low risk±bene®t ratio, as would be expected from theselective serotonin reuptake inhibitors. The SSRIsshould now be accepted as the antidepressants ofchoice in the physically ill elderly.

Further work is required to determine thespeci®c e�ect of various physical illnesses on theprevalence of depression in elderly patients and itsresponse to treatment.

ACKNOWLEDGEMENTS

Thanks to Jackie Turner at Pharmakopius Inter-national, Reading, for statistical support; and toLilly Industries for funding the study, numberBIY BP HC55.

REFERENCES

Akiskal, H. S., King, D., Rosenthal, T, Robinson, D.and Scott-Strauss, A. (1981) Chronic depressions part1. Clinical and familial characteristics in 137 probands.J. A�ect. Disord. 3, 297±315.

Ames, D. (1990) Depression among elderly residentsof local authority residential homes: Its nature andthe e�cacy of intervention. Brit. J. Psychiat. 156,667±675.

Baldwin, R. C. and Jolley, D. J. (1986) The prognosis ofdepression in old age. Brit. J. Psychiat. 149, 574±583.

Burvill, P. W. (1990) Quanti®cation of physical illness inpsychiatric research in the elderly. Int. J. Geriatr.Psychiat. 5, 161±170.

Evans, M. E. (1993) Depression in elderly physically illin-patients: A 12-month prospective study. Int. J.Geriatr. Psychiat. 8, 587±592.

Evans, M. E., Burgess, H. and Gore-Rees, E. (1995)Long term care: Reducing morbidity in residents andsta�. Psychiatr. Bull. 19, 612±615.

Evans, M. E., Copeland, J. R. M. and Dewey, M. E.(1991) Depression in the elderly in the community:E�ect of physical illness and selected social factors.Int. J. Geriatr. Psychiat. 6, 787±795.

Evans, M. E., Hammond, M., Wilson, K. C. M., Lye, M.and Copeland, J. R. M. (1997) Placebo controlledtreatment trial of depression in elderly physically illpatients. Int. J. Geriatr. Psychiat. 12, 817±824.

Evans, M. E. and Lye, M. (1992) Depression in thephysically ill, an open study of treatment with the5-HT reuptake inhibitor ¯uoxetine. J. Clin. Exp.Gerontol. 14, 297±307.

Feldman, E., Mayou, R., Hawton, K., Ardern, M.and Smith, E. B. O. (1987) Psychiatric disorder inmedical in-patients. Quart. J. Med., New Series 63,241, 405±412.

Folstein, M. F., Folstein, S. E. andMcHugh, P. R. (1975)`Mini Mental State'. A practical method for gradingthe cognitive state of patients for the clinician.J. Psychiatr. Res. 12, 189±198.

# 1997 John Wiley & Sons, Ltd. INT. J. GERIAT. PSYCHIATRY, VOL. 12: 1189±1194 (1997)

TREATMENT OF DEPRESSION: RESPONSE OF PHYSICALLY ILL PATIENTS 1193

Gregory, R. J., Jimerson, D. C., Walto, B. E., Daley,J. and Paulsen, R. H. (1992) Pharmacotherapy ofdepression in the medically ill: Directions for futureresearch. Gen. Hosp. Psychiat. 14, 36±42.

Hamilton, M. (1960) A rating scale for depression.J. Neurol. Neurosurg. Psychiat. 23, 56±62.

Hawton, K. (1981) The long term outcome of psychiatricmorbidity detected in general medical patients.J. Psychosom. Res. 25, 237±243.

Hendler, N. (1984) Depression caused by chronic pain.J. Clin. Psychiat. 45(3sec2), 30±36.

Kay, D. W. K. (1962) Outcome and cause of deathin mental disorders of old age: A long term follow-upof functional and organic psychoses. Acta Psychiatr.Scand. 38, 249±276.

Koenig, H. G., Goli, V., Shelp, F., Kudler, H. S., Cohen,H. J. and Blazer, D. G. (1992) Major depression inhospitalised medically ill older men: Documentation,management and outcome. Int. J. Geriatr. Psychiat. 7,25±34.

Lakshmanan, M., Mion, L. C. and Frengley, J. (1986)E�ective low dose tricyclic antidepressant treat-ment for depressed geriatric rehabilitation patients:A double-blind study. J. Am. Geriatr. Soc. 34,421±426.

Magni, G., De Leo, D. and Schifano, F. (1985)Depression in geriatric and adult medical inpatients.J. Clin. Psychol. 41, 337±344.

Mayou, R., Hawton, K. and Feldman, E. (1988)What happens to medical patients with psychiatricdisorder? J. Psychosom. Res. 32, 541±549.

Meats, P., Timol, M. and Jolley, D. (1991) Prognosisof depression in the elderly. Brit. J. Psychiat. 159,659±663.

Murphy, E. (1983) The prognosis of depression in oldage. Brit. J. Psychiat. 142, 111±119.

Popkin, M. K., Callies, A. L. and MacKenzie, T. B.(1985) The outcome of antidepressant use in themedically ill. Arch. Gen. Psychiat. 42, 1160±1163.

Robinson, R. G., Kubos, K. L., Starr, L. B. and Price,T. R. (1983) A two year longitudinal study of post-stroke mood disorders: Findings during the initialevaluation. Stroke 14, 736±741.

Rodin, G. and Voshart, K. (1986) Depression in themedically ill: An overview. Am. J. Psychiat. 143,696±705.

Schleifer, S. J., Macari-Hinson, M. M., Coyle, D. A.et al. (1989) The nature and course of depressionfollowing myocardial infarction. Arch. Int. Med. 149,1785±1789.

Stern, M., Pascale, L. and McLoone, J. B. (1976)Psychosocial adaptation following an acute myo-cardial infarction. J. Chron. Dis. 29, 513±526.

Stimmel, G. L. and Escobar, J. I. (1986) Antidepressantsin chronic pain: A review of e�cacy. Pharmacotherapy6, 262±267.

INT. J. GERIAT. PSYCHIATRY, VOL. 12: 1189±1194 (1997) # 1997 John Wiley & Sons, Ltd.

1194 M. EVANS ET AL.