Drug and ECT treatment of depression in the elderly, 1996–2001: a literature review

Drug and ECT Treatment of Depression in the Elderly, 1996 –2001: A Literature Review Carl Salzman, Eileen Wong, and B. Cody Wright A computer-based literature search of all antidepressant and electroconvulsive therapy (ECT) treatment studies published between 1995 and September 2001 was conducted. In addition, a review of published chapters, review articles, and metaanalyses was also conducted. Articles were categorized into those reporting comparative studies, those in which the therapeutic agent was not compared with another, articles about ECT, and review articles. These recent publications support the conclusions from prior reviews that antidepressants and ECT are effective and safe treatments for depressed elderly patients. Differences in efficacy and side effects appear to be slight among the various types of antidepressants. Research studies of depressed elderly increased markedly since 1995 compared with all previous years although more studies are still necessary. Biol Psychiatry 2002;52: 265–284 © 2002 Society of Biological Psychiatry Key Words: Elderly, depression, antidepressant, dysthymia, ECT

Introduction

I

n 1994, an National Institute of Mental Health (NIMH)sponsored Consensus Conference on the diagnosis and treatment of late-life depression (Schneider 1994) included a literature review and two meta-analyses of drug and ECT treatment studies of depression published up to the time of the conference (Salzman 1994; Sackheim 1994; Klawansky 1994; Schneider 1994). The primary goal of this present review, prepared for a second consensus conference on late-life depression held in October 2001 in Washington, DC, was to examine studies of drug and ECT treatment of depression in the elderly published since the last consensus conference. Since the audience for the second consensus conference included nonresearchers, an additional goal was to provide a survey of drug and ECT treatment recommendations from the clinical as well as research literature. From the Department of Psychiatry, Harvard Medical School, Massachusetts Mental Health Center, Boston, Massachusetts. Address reprint requests to Dr. C. Salzman, Harvard University, Massachusetts Mental Health Center, 74 Fenwood Road, Boston MA 02115. Received October 16, 2001; revised December 28, 2001; accepted January 7, 2002.

© 2002 Society of Biological Psychiatry

Methods and Materials Medline and Paperchase literature reviews were conducted and all English language available publications from 1995 through September 2001 were assembled. Criteria for inclusion of a publication in this review were: 1) All subjects had to be 65 years or older (although in a few studies, subjects 60 years and older were included, but the mean age was substantially over 65 years). 2) Studies had to have been at least 4 weeks in length, using standardized depression assessments (a few shorter studies were included that focused on sleep, pharmacokinetics, or EKG measures only). Publications were divided into one of four categories as reflected in the four tables accompanying this review. The first category (Table 1) includes comparative research studies. In this category one drug was compared with one or more other active drugs, or with placebo. A few studies in this category compared the effects of augmentation treatment against no augmentation, and some included a comparison with psychotherapy. The second category includes studies in which there was no comparison. Most of these studies were open, single-blind studies, or follow-up studies (Table 2). The third category focuses exclusively on electroconvulsive therapy in the elderly. Comparative and noncomparative studies were combined for this category (Table 3). The fourth category includes review papers, metaanalyses, and selected book chapters on drug or ECT treatment of depression in the elderly. Although an attempt was made to be comprehensive in compiling this list, it was not possible to review all chapters or all review papers published since 1995. Letters to the editor, editorial comments, and articles in unrefereed journals were not included.

Results One of the conclusions of the prior Consensus Conference was the need for increased research into the treatment of depressed elderly patients. It is apparent that researchers and clinicians have responded this need. A total of 97 0006-3223/02/$22.00 PII S0006-3223(02)01337-9

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Table 1. Comparative Treatment Studies Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age Study duration

Ackerman et al 2000 Bondareff et al 2000

Fluoxetine 20 vs. PBO Sertraline 50 –150 vs. nortriptyline 25–100

671 outpatients. DSM-III-R 210 outpatients. DSM-III-R

⬎60

Brion et al 1996

Tianeptine 25–37.5 vs. Mianserin 20 Paroxetine vs. nortriptyline Paroxetine 23.3– 26.4 vs. PBO

299 DSM-III-R

⬎70

Bump et al 2001 Burrows et al in press Buysse et al 1997

116 outpatients. SADS-L ROC 20 frail NH residents. DSM III-R 119 SADS; RDC Nortriptyline, nonpsychotic. adjunct lorazepam 1.4

67.8

6 weeks 12 weeks

26 weeks

72.5

24 weeks

87.9

8 weeks

68

Sleep study

Rating scales HAM-D, CGI, GDR, PGI ADS, MMSE, POMS, Q-LES-Q, HAM-D, WAIS MADRS, HAM-D

Outcome Fluox ⫽ PBO for moderately severely depressed patients. Sert ⫽ NT; ⬎age 70 sert ⬎NT. Safety profile sert ⫽ NT. Equal efficacy.

HAM-D, MMSE, Equal efficacy in relapse and GAS, MATTIS recurrence prevention. Parox ⫽ PBO for minor HAM-D, Cornell depression in NH residents. Depression, CGI, GDS, MMSE HAM-D, BDI, GAS, LZ useful for treating anxiety Sleep measures in elderly depressed patients; does not slow antidepressant response. HAM-D Only modest response in medically ill patients. Sert ⬎fluox for efficacy, HAM-D, HAM-A, tolerability, cognitive CGI, POMS, Qimprovement. LES-Q, WAIS-R, DSST CGI, MADRS, Sert ⫽ IMI for efficacy and MMSE tolerability.

Evans et al 1997

Fluoxetine vs. PBO

62 medically ill.

80.4

8 weeks

Finkel et al 1999

Sertraline 50 –100 vs. fluoxetine 20 – 40

75 outpatients. DSM-III-R

74

12 weeks

55 outpatients. Moderately depressed. Moderately demented. 671 outpatients. DSM-III-R 80 in- and outpatients. DSM-IV 12 outpatients. DSM-III-R

68.5

6 weeks

60⫹

6 weeks

Weight

No weight change.

75

2 weeks

HAM-D

76.2

2 years

MADRS, GDS

Heiligenstein et al Fluoxtine vs. PBO 261 outpatients. 1995 Major depression. Høyberg et al 1996 Mirtazapine 15– 45 115 in- and outpatients. vs. amitriptyline DSM-III 30 –90 Karlsson et al 2000 Citalopram 20 – 40 336 mild to moderate vs. mianserin 30 – dementia and 60 depression. Katona et al 1999 Reboxetine 4 – 6 vs. 347 in- and imipramine 50 – outpatients. DSM-III-R 100 95 DSM-III-R Kin et al 1997 Moclobemide 400 vs. NT 75 vs. PBO

60⫹

6 weeks

70.5

6 weeks

Health Status Survey HAM-D, MADRS, CGI

Sleep deprivation added to antidepressants produces rapid response. Significantly ⬍SE in PBO group; slightly ⬎risk of relapse. Fluox ⬎⬎ PBO

75

12 weeks

MADRS, CGI

Equal efficacy; worse outcome in pts with dementia.

74

8 weeks

HAM-D, CGI

Equal efficacy; IMI better in dysthymia.

71

7 weeks

DST

Koran et al 1995

68

6 weeks

HAM-D, GDS

DST positive; patients had better NT response; DST negative patients better MOC response. 43% response; 28% remission by week 4; early responders do not always predict final response.

Forlenza et al 2000 Sertraline 50 vs. imipramine 150

Goldstein et al 1997 Green et al 1999

Hardy et al 1997

Fluoxetine 20, vs. PBO Paroxetine vs. nortriptyline vs. PBO Adjunct lithium vs. PBO

Fluoxetine 20 vs. PBO

671 outpatients. DSM-III-R

Mirt ⫽ AMI for efficacy and tolerability.

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Table 1. Continued Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age

Study duration

Rating scales

Outcome

MADRS, HAM-D, CGI

Kyle et al 1998

Citalopram 20 – 40 vs. amitriptyline 50 –100

365 private practice patients. DSMIII-R

73

8 weeks

Liu et al 1998

TCAs, SSRIs

8239 N/A

66⫹

1 year

Lyketos et al 2000

Sertraline 12–150 vs. PBO

22 outpatients with Alzheimer’s

77

12 weeks

HAM-D, CSDD, PDRS, MMSE

Magai et al 2000

Sertraline 25–100 vs. PBO

31 NH residents with Alzheimer’s

89.2

8 weeks

CSDD, GS, CMAI

Mahapatra, 1997

Venlafaxine 50 –150 vs. Dothiepin 50 –150 Nortriptyline 25 vs. paroxetine 10

92 in- and outpatients. DSM-III-R 62 in- and outpatients. Clinical diagnosis. 37 outpatients remitted depression. SADS-1 RDC

74.5

6 weeks

HAM-D, MADRS

Cit ⫽ IMI for efficacy; IMI ⬎Cit for side effects. Retrospective case review. Equal risk of hip fracture. Sert ⬎PBO; full remission 25%, partial 50%. Sert ⫽ PBO; sert ⬎PBO for facial signs of depression. Equal efficacy.

71.6

6 weeks

EPS

NT ⫽ parox

N/A

2–3 years

Side effects

Maintenance study. Side effects related to residual depression rather than NT. Maintenance study. Equal efficacy; more EPS and falls in NT ⫹ perphen group. Significant EKG changes reverted to baseline with PBO; cardiac disease patients had no worse changes than noncardiac patients. TCA, MAOI ⬎others, acute treatment and maintenance; TCA ⫽ SSRI ⫽ MAOI ⫽ atypical, side effects. Parox ⫽ NT for efficacy and tolerability. NT ⫹ perphen ⫽ NT ⫹ PBO for efficacy and tolerability.

Mamo et al 2000

Marraccini et al 1999

Nortriptyline vs. PBO

Meyers et al 2001

Nortriptyline vs. perphenazine (12–16 mg); NT ⫹ PBO

28 delusional depression. SCID-P

71.8

26 weeks

HAM-D, Barnes Akathisia; Simpson Angus; AIMS

Miller et al 1998

Nortriptyline vs. PBO

50 SADS-L RDC

N/A

7 weeks; 1 year

EKG

Mittmann et al 1999

TCA vs. SSRI vs. MAOI vs. atypical

213 outpatients. DSM-III-R

75.5

2 years

MADRS

Mulsant et al 1999

Paroxetine 10 –30 vs. nortriptyline 25–100 Nortriptyline 63.2– 76.3, perphenazine 18.9 –19.3, PBO

80 in- and outpatients. DSM-IV 30 in- and outpatients with severe and psychotic depression. DSM-IV 109 in- and outpatients. DSM-III-R

75

6 weeks

HAM-D, MMSE, UKU

72.5

6 weeks

HAM-D, BPRS, side effects

60⫹

7 weeks

Mulsant et al 2001

Nair et al 1995

Moclobemide 400 vs. nortriptyline 75 vs. PBO

NT⬎ mocl⬎PBO remission rates.

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Table 1. Continued Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age

Study duration

Rating scales

Navarro, 2001

Citalopram 30 – 40 vs. nortriptyline 50 –100

58 outpatients with moderate to severe depression. DSM-IV

70.6

12 weeks

HAM-D, MMSE, UKU

Newhouse et al 2000

Sertraline 50 –100 vs. fluoxetine 20 – 40

236 outpatients. DSM-III-R

68

12 weeks

Nobler et al 2000

Nortriptyline, sertraline 150

20 dysthymic disorder outpatients. DSM-III-R.

67

6-9 weeks

HAM-D, HAM-A, CGI, MADRS, Q–LES–Q, MMSE HAM-D

Oslin, 2000

Sertraline 25–100 vs. nortriptyline 10 – 80

97 Frail NH residents. Clinical diagnosis.

83.1

8 weeks

MMSE, PSMS, HAM-D

Petracca et al 1996

Clomipramine vs. PBO

72

14 weeks

HAM-D, MMSE

Pollock et al 1998

Paroxetine 20 –30 vs. NT

21 outpatients with Alzheimer’s DSM III-R 61 N/A

73.2

6 weeks

UKU SE Rating Scale

Pollock et al 2000

Paroxetine, nortriptyline

96 DSM-IV

72

12 weeks

HAM-D

Rahman et al 1991

Fluvoxamine 100 – 200 vs. Dothiepin 100 –200 Nortriptyline, adjunct lithium 600, perphenazine 4, paroxetine 20

52 inpatients. DSM-III

6 weeks

MADRS

16 weeks

HAM-D, BDI, GAS, PAS, RSQI, PSS

Reynolds et al 1996b

Nortriptyline vs. PBO

148

67.9

24 weeks

HAM-D

Reynolds et al 1997

Nortriptyline vs. PBO

40 outpatients. SADS-L RDC

61.3

1 year

Sleep study

Reynolds et al 1996a

158 in- and outpatients. SADS-L

⬎64 68.3

Outcome NT better than cit; remission of severe depression; NT better than cit for autonomic side effects. Sert ⫽ fluox; sert better than fluox for cognitive improvement. NT ⫽ sert; responders show reduced cerebral blood flow in frontal and anterior temporal regions. NT better than sert for efficacy; NT ⫽ sert for tolerability. CMI ⬎⬎PBO for remission. A serum anticholinergicity NT better than paroxetine. Serotonin transporter gene allele variations correlate with response to parox but not NT. Equal efficacy.

Worse response, relapse rates, and remission rate in adjunctive medication patients. Maintenance study. Elderly patients responded as well as, but more slowly than, midlife depressives. Maintenance study. NT patients had later sleep onset; did not maintain better sleep; increased total REM activity; effective treatment associated with increased delta sleep ratio and increased REM.

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Table 1. Continued Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age

Study duration

Rating scales

Reynolds et al 1999b

Nortriptyline 80 – 120 ng/mL, nortriptyline 40 – 60 ng/mL

41 SADS-RDC

68

3 years

HAM-D

Reynolds et al 1999a, c

Nortriptyline vs. PBO. Interpersonal therapy.

180 Major depression unipolar, nonpsychotic.

70⫹

1 year

HAM-D

Roth et al 1996

Moclobemide 400 vs. PBO

726 in- and outpatients. DSM-IV

73.6

6 weeks

HAM-D, MMSE, SCAG, CGI, BG-P

Schneider, 1995

Fluoxetine 20, ERT, vs. PBO Imipramine vs. buspirone vs. PBO Fluoxetine 20 vs. PBO

367 outpatients. DSM-III-R 177

67.9

6 weeks

HAM-D, GDS

72

8 weeks

HAM-D, CGI, HAM-A

671 outpatients. DSM-III-R

67.7

6 weeks

HAM-D

Streim et al 2000

Nortriptyline 10 –13 vs. nortriptyline 60 – 80

69 Frail NH. DSMIV

79.5

10 weeks

HAM-D, CGI, GES

Taylor et al 1999

Nortriptyline vs. PBO

27 outpatients. SADS-L RDC

N/A

Discontinuation study

HAM-D

Taylor, 1999

Nortriptyline vs. PBO

25

N/A

16 weeks

Clinical evaluation. HAM-D

Thapa et al 1998

TCA 50⫹, SSRI 20⫹, trazodone

2428 NH residents

82

180 days

Number of falls

Tignol et al 1998

Milnacipran 100 vs. imipramine 100

147 in- and outpatients. DSMIII-R

74.1

8 weeks

HAM-D, MADRS, CGI, COVI Anxiety, MMSE, WAIS

Schweizer et al 1998 Small et al 1995

Outcome Better outcome with higher blood levels, but increased constipation. Equal recurrence. Acute maintenance study. Drugs combined with IPT; higher recurrence in 70⫹ compared with younger patients. Mocl ⫽ PBO; Mocl ⬎PBO in demented patients. ERT augmented fluox response. IMI⬎Buspar⬎PBO.

Fluox markedly superior to PBO, but no response predictors identified. Regular dose slightly better than low dose; low dose much superior in cognitively impaired subjects. NT decreases REM time and %; increases REM density; REM measures revert with response. After NT withdrawal, patients severely depressed before treatment relapsed; less severely depressed were well maintained with interpersonal psychotherapy. TCA ⫽ SSRI in risk of falls of NH residents. Equal therapeutic efficacy; more anticholinergic SE with IMI.

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Table 1. Continued Author

Drug mg/d

Sample size and diagnostic criteriaa

Van Laar et al 1995

Nefazodone 200 – 400 vs. imipramine 100 vs. PBO

24 volunteers. No diagnosis.

Wallace et al 1995

Methylphenidate vs. PBO

13 chronically ill. Medical/surgical inpatients.

Walters et al 1999

Paroxetine 20 – 40 vs. nortriptyline 20 –75

Weber et al 1999

Nortriptyline vs. paroxetine

Weihs et al 2000

Bupropion 100 –300 vs. paroxetine 10 – 40 Trimipramine vs. fluoxetine

Wolf et al 2001

Mean age

Study duration

Rating scales

7 days

Driving tests

72.3

8 days

HAM-D, MMSE

40 inpatients with moderate depression. DSM-IV 32 in- and outpatients. DSM-IV 100 outpatients. DSM-IV

75

18 months

HAM-D, MMSE

74

12 weeks

Weight study

70

6 weeks

HAM-D, HAM-A, CGI

19 in- and outpatients. DSM-III-R

70

6 weeks

Sleep study

Outcome IMI impaired driving, high dose of nefaz also impaired driving; high doses of both impaired memory. Rapid resolution of SX in older medically ill patients. Maintenance study. Parox ⫽ NT for efficacy, relapse prevention. No differential weight change. Bup ⫽ Parox for efficacy and tolerability. Early antidepressant effects independent of REM suppression.

AIMS, Abnormal Involuntary Movement Scale; BUP, bupropion; CGIII, Clinical Global Impression Scale; Cit, citalopram; CSDD, Cornell Scale for Depression in Dementia; DSMII, Diagnostic and Statistical Manual, III; DSST, Digit Symbol Substitution Test; DST, Dexamethasone Suppression Test; EPS, extra pyramidal symptoms; Fluox, fluoxetine; GAS, Global Assesment Scale; GDS, Geriatric Depression Scale; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; IMI, imipramine; LZ, lorazepam; MADRS, Montgomery-Asberg Depression Rating Scale; MAOI, monoamine oxidase inhibitor; Mattis, Mattis Dementia Rating Scale; MMSE, Mini Mental State Exam; NH, nursing home; NT, nortriptyline; PBO, placebo; PDRS, Psychiatric Diagnostic Screening Questionnaire; Perphen, perphenazine; POMS, Profile of Mood States; PSS, Perceived Stress Scale; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; RDC, Research Diagnostic Criteria; SADS-L, Schedule for Affective Disorders and Schizophrenia—Lifetime; SCAG, Sandoz Clinical Assessment for Geriatrics; SCID-P, structured clinical interview, diagnosis-patient; SE, side effects; SSRI, selective serotonin reuptake inhibitor; SX, symptoms; TCA, tricyclic; UKU, Udvalg for Kliniske Undersogelser; WAIS, Wechsler Adult Intelligence Scale. a Not available for all studies.

antidepressant reports and 12 ECT reports were published during the period of this review. A total number of 33,167 subjects were directly studied, surveyed or followed. Thus, during the past 6 years there have been 10 times more elderly subjects in published studies than in all of the preceding years combined. The mean age in the 72 studies with available age information was 72.8 years. Eight reports focused on subjects with a mean age greater than 80; an additional 14 studies were of subjects whose mean age was between 75 and 80 years. The mean length of acute treatment studies was 9 weeks (58 studies, excluding kinetic and sleep studies). The most common rating instruments were: HAM-D (57 studies), CGI (17 studies), Mini-Mental Status Exam (19 studies), and the Montgomery Asberg Depression Rating Scale (15 studies).

Comparative Treatment Studies (Table 1) Sixty comparative studies were conducted. Most compared one drug against another or several others; 27 compared antidepressant against placebo. Different aspects of studies were commonly published in separate reports, so the number of publications does not reflect the number of individual studies performed. Nortriptyline was the most common drug studied (25 reports) followed by fluoxetine (10), paroxetine (9), and sertraline (8). Taken together, these comparative studies suggest: 1) Placebo is still commonly used in comparative treatment studies of geriatric depressions. 2) Eleven studies compared the efficacy of TCAs (primarily nortriptyline) with SSRIs. Eight studies

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Table 2. Antidepressant Trials in the Elderly Without Comparisons Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age

Study duration

Rating scales

Outcome 95% improved by 1 year. Recovery rate similar to that in younger depressed patients; late age of onset predicts slow recovery. Safe and effective except for more severely depressed patients; good prophylactic efficacy. Effective, well tolerated.

Aguglia, 2000 Alexopoulos, 1996

Reboxetine All antidepressants

160 Major depression 86 In- and outpatients RDC; moderate, severe, and psychotic patients.

65–94 74.9

1 year 18.2 months

CGI, HAM-D HAM-D, CSDD, GDS, MMSE, Mattis Dementia

Amore et al 1997

Venlafaxine

28 Outpatients. Major depression.

⬎65

24 months

HAM-D

Arranz and Ros 1997 Andreoli et al 1999 Bergmann et al 2000

Sertraline 50 –200

1437 Outpatients

68

8 weeks

MADRS

Reboxetine 4 – 8

12 Major depression and dysthymia 12 Healthy volunteers

75– 87

4 weeks

CGI, HAM-D

81

24 hours

Kinetic study

Bodani et al 1999

Dexamethasone

N/A

N/A

N/A

Bump et al 1997

Paroxetine

2 Treatment-resistant depression 13 Outpatients. SADS-L RDC

N/A

12 weeks

HAM-D

Devanand et al 1997

Fluoxetine

29 Outpatients. Dysthymia DSMIII-R

67.5

13 weeks

HAM-D, Cornell Dysthymia, CGI

Dew et al 1997

Nortriptyline

95 SADS-L RDC

67.1

18 weeks

HAM-D

Dierick, 1996

Venlafaxine 50 – 150 Nortriptyline 25– 75, phenelzine 15–30, ECT

116 Outpatients

52 weeks

MADRS, CGI

101 N/A

73.9

14

HAM-D

Nortriptyline, phenelzine, lithium augmentation Nortriptyline, phenelzine, lithium, ECT

99 Outpatients. DSM-III-R

73.9

14 weeks

Hospital anxiety and depression

84 Outpatients. DSM-III-R

73.9

2 years

HAM-D

Flint and Rifat 1996

Flint and Rifat 1997a, b

Flint, 1997c, 1997

Reboxetine 4

⬎65

7 improved; tachycardia in 5. Clearance reduced; appropriate starting dose 4 mg/d. Effective for treatmentresistant depression. 62% improvement following 1 night sleep deprivation. 12 responders among patients with dysthymic disorder; 6 relapsed over next 24 weeks. History and EEG sleep characteristics can predict response to treatment. Rapid response associated with low stress prior to onset, late onset age, milder SX, and higher % REM and delta sleep. Effective for 2/3 of subjects by 2 months. Phenelzine effective, but slower in NT nonresponders; poor response to ECT in treatment failures. Sequential treatment. Anxious patients less responsive to treatment. Maintenance study. Maintenance treatment with full-dose antidepressants resulted in 74% cumulative probability of surviving without relapse or recurrence. Anxious patients had a higher relapse rate over a 2year follow-up period.

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Table 2. Continued Author

Sample size and diagnostic criteriaa

Drug mg/d

Flint and Rifat 1999

Nortriptyline, phenelzine

Flint and Rifat 2000

Nortriptyline, phenelzine

Flint and Rifat 2001

Gutierrez and Abramowitz 2000 Khan et al 1995

Mean age

Study duration

Rating scales

Outcome

HAM-D, MMSE, Life events HAM-D

Discontinuation study. Cumulative probability of recurrence 60.6%. Maintenance study. Maintenance treatment with full-dose antidepressants resulted in 70% cumulative probability of surviving without relapse or recurrence. Responders to 1st drug had 18% relapse; those who needed a second drug after failing the first had 67% relapse rate. 30% increase in elimination half-life.

21 1st-episode major depression. DSM-IIIR 38 Outpatients. DSMIII-R

74.4

2 years

72.9

208 weeks

Nortriptyline, phenelzine

74 Outpatients. Nonpsychotic; unipolar.

72.9

4 years

HAM-D, HAM-A

Citalopram 10 – 40

24 Volunteers. No diagnosis.

5 weeks

Kinetic study

Venlafaxine 75– 225

58 Outpatients. DSMIII-R

71.0

12 months

CGI, Symptom check list, quality of life

Kin et al 1996

Nortriptyline 75

38

71

7 weeks

Pharmacokinetic study

Kirby and Ames 2001

SSRIs

736 N/A

N/A

N/A

Lavretsky and Kumar 2001

Methylphenidate, citalopram

10 Outpatients. DSMIV

8 weeks

HAM-D

Little, 1998

Nortriptyline 78.7

159 SADS-L

26 weeks

HAM-D

Marar et al 2000

Paroxetine

66

5 hours

Mentre et al 1998

Fluoxetine 20

5 Depressed volunteers DSM-IV 16 N/A

⬎60

6 weeks

Water-load testing MADRS

Mulsant et al 1997

73

12 hours

Kinetic study

Nobler et al 1996

Nortriptyline 56, perphenazine 19 Fluoxetine 20 – 60

67.2

13 months

Orengo et al 1996

Fluoxetine 20 mg

71.8

10 months

Oslin, 2000

Alcohol

77.2

3– 4 months

HAM-D, CGI, CDRS HAM-D, BPRS, MMSE GDS, MMSE

Rigler et al 2001

SSRIs

N/A

N/A

25 Inpatients. Psychotic depression. 23 Outpatients. DSMIII-R 31 Inpatients. DSM III-R 2666 Inpatients. DSMIV

6000 Nursing home.

N/A

⬎65

79.8

⬎65

Effective antidepressant; headache, nausea, insomnia, dry mouth common. 80% had blood levels within therapeutic range. Hyponatremia common, developing 2 weeks after drug initiation. Significant augmentation of citalopram effect on 8/10. 11.9% did not experience remission and 18.4% were treatment resistant. Parox does not impair water excretion. Responders had low RBC count, lower plasma-free tryptophan. Perphen increases NT blood level. Effective for dysthymia; well tolerated. Moderate improvement; well tolerated. Alcohol does not impair treatment response, but alcohol increases disability from depression. SSRIs as likely to cause weight gain as weight loss, both marginal significance.

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Table 2. Continued Author

Drug mg/d

Sample size and diagnostic criteriaa

Mean age ⬎65

Study duration

Rating scales

Ronfeld et al 1997

Sertraline 200

Rosen et al 2000

Sertraline

Saiz-Ruiz et al 1998

Tianeptine 25

22 volunteers. No diagnosis. 12 minor depression. NH DSM-IV 63 outpatients.

Sweet et al 1995

Bupropion

6 N/A

Weintraub, 2001

Nortriptyline 54

10 in- or outpatients. DSM-IV

76.8

2– 8 weeks

Clinical evaluation

Williams et al 2000

Paroxetine 10 – 40

71

11 weeks

HSCL, HAM-D

Young et al 1999

Nortriptyline

415 outpatients. Dysthymia and minor depression; primary care setting. DSM-IIIR; DSM-IV 15 inpatients. RDC

75.2

6 weeks

CT study

Zimmer et al 1997

Venlafaxine 50 – 250

18 serious medical comorbidity.

73

3–9 months

Blood pressure, CGI

83.2 ⬎65

9 days

Kinetic study

6 weeks

HAM-D, GAS

3 months

CGI, MADRAS, HAM-D, Zung, MMSE Pharmacokinetic study

Outcome Metabolism slowed in elderly males. Minor depression in NH: 75% remission. Effective and well tolerated.

Decreased clearance and prolonged half-life in elderly; elderly at risk for accumulation of bup and its metabolites. 70% response to addition or substitution of NT in SSRI nonresponders. Paroxetine showed moderate benefit; superior to psychotherapy.

Worse response with larger ventricles. No significant BP increase.

AIMS, Abnormal Involuntary Movement Scale; BUP, bupropion; CGIII, Clinical Global Impression Scale; Cit, citalopram; CSDD, Cornell Scale for Depression in Dementia; DSMII, Diagnostic and Statistical Manual, III; DSST, Digit Symbol Substitution Test; DST, Dexamethasone Suppression Test; EPS, extra pyramidal symptoms; Fluox, fluoxetine; GAS, Global Assesment Scale; GDS, Geriatric Depression Scale; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; IMI, imipramine; LZ, lorazepam; MADRS, Montgomery-Asberg Depression Rating Scale; MAOI, monoamine oxidase inhibitor; Mattis, Mattis Dementia Rating Scale; MMSE, Mini Mental State Exam; NH, nursing home; NT, nortriptyline; PBO, placebo; PDRS, Psychiatric Diagnostic Screening Questionnaire; Perphen, perphenazine; POMS, Profile of Mood States; PSS, Perceived Stress Scale; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; RDC, Research Diagnostic Criteria; SADS-L, Schedule for Affective Disorders and Schizophrenia—Lifetime; SCAG, Sandoz Clinical Assessment for Geriatrics; SCID-P, structured clinical interview, diagnosis-patient; SE, side effects; SSRI, selective serotonin reuptake inhibitor; SX, symptoms; TCA, tricyclic; UKU, Udvalg for Kliniske Undersogelser; WAIS, Wechsler Adult Intelligence Scale. a Not available for all studies.

reported equivalent efficacy; three reported superior efficacy of tricyclics. 3) Although side effects were present when antidepressants were given, and tricyclics had slightly more frequent and intense side effects that nontricyclic antidepressants, the elderly patients in these studies tolerated all antidepressants quite well, and in some cases, there were no differences among classes of antidepressants in producing side effects. Three studies in a nursing home reported that tricyclics were better tolerated than SSRIs. In one very large survey, tricyclics and SSRIs were an equivalent risk for falls and hip fractures. 4) Five studies examined patients in nursing homes. In one study of very elderly, frail, depressed patients and another with depressed patients who also had Alzheimer’s disease, drug was not superior to pla-

cebo. In the remaining three studies in which drugs were efficacious, there was no difference in either efficacy or side effect profile between tricyclics and SSRIs; lower doses were more effective in the patients with marked cognitive impairment. 5) A benzodiazepine (lorazepam) was helpful in the treatment of anxious depressed elderly patients, and a neuroleptic (perphenazine) was helpful in treatment of patients who were psychotic. Use of these drugs did not impair or delay the therapeutic antidepressant response, and both drugs were well tolerated. 6) Five studies examined the effect of medication on depressed patients who were also demented. In two of the studies, the depressive symptoms remitted, in two others there was meaningful clinical response, and in the fifth, there was therapeutic efficacy but

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Table 3. Electroconvulsive Therapy (ECT) in the Elderly Author Brodaty et al 2000 De Carle and Kohn 2000 Flint and Rifat 1998a

Flint and Rifat 1998b Gormley et al 1998 Manly et al 2000

O’Connor et al 2001 Philibert et al 1995 Rao and Lyketosos 2000

Sample size

Mean age

81

65–74, 75⫹

N/A

N/A

Rating scales HAM-D

Equal efficacy; older patients more likely to develop dementia. ECT increases risk of falls in the elderly.

N/A

126

74.7

HAM-D

25

60⫹

HAM-D

Psychotic depressed patients at ⬎risk of relapse or recurrence than nonpsychotic pts; tricyclic monotherapy following ECT of limited usefulness. ECT ⬎⬎ NT ⫹ perphen for psychotic depression; slower response to meds. 85% marked or moderate improvement.

⬎75 78

93

⬎75

Clinical evaluation

73.8

HAM-D

108

71

EKG study

31

N/A

Stoudemire et al 1998 Tew et al 1999

39

71

268

60 –74, 75⫹

Tomac et al 1997

34

⬎85

Outcome

MADRS, MMSE

HAM-D, LIFE HAM-D HAM-D, HAM-A, MMSE, BPRS

Better outcome and fewer side effects with ECT than pharmacotherapy; longer length of stay with ECT. Older patients had higher remission rates than younger and middle-aged adults. ECT ⬎⬎ pharmacotherapy for efficacy; no longterm side effects. ECT effective treatment for depression with dementia; improvements in mood and cognition; multiple treatments necessary; 1⁄2 of patients developed delirium. 90% recovery rate; 29% relapse rate despite maintenance antidepressants. Best response in 60 –74 followed by 75⫹; well tolerated, even in oldest patients. Very elderly with concurrent medical problems tolerated ECT well.

BPRS, Brief Psychiatric Rating Scale; EKG, electrocardiogram; HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression; IMI, imipramine; LZ, lorazepam; LIFE, Longitudinal Interval Follow-up Evaluation; MADRS, Montgomery-Asberg Depression Rating Scale; MAOI, monoamine oxidase inhibitor; MMSE, Mini Mental State Exam; NT, nortriptyline.

the antidepressant was not as effective in patients with more severe dementia. 7) There were six studies of MAO inhibitors. In four of the studies the MAO inhibitor was less effective than other antidepressants or was equivalent to placebo; it was equal to other antidepressants in one study and better (for anxious depressed elderly patients) in one study. 8) The less the therapeutic response to antidepressants, the higher the relapse or recurrence rate; relapse or recurrence was common when treatment was withdrawn.

Noncomparative Studies Antidepressant trials without drug comparisons are shown in Table 2. Some studies show more than one drug listed, but in these cases the drugs were not actually compared with each other but were given consecutively. Thirty-six reports describing the effect of an antidepressant in elderly subjects without a comparative medication were published since the first consensus conference; two were pharmacokinetic studies in normal elderly volunteers without de-

pression. Overall, these noncomparative studies support the efficacy of antidepressants in the elderly, their use being well tolerated. 1) Four studies focused on outpatients with dysthymia or minor depression; all reported the efficacy of an SSRI antidepressant or reboxetine. 2) Relapse and recurrence was common in these reports, but switching antidepressant (e.g., nortriptyline for SSRI nonresponders; MAO inhibitors for TCA nonresponders) was often effective in producing a response. 3) Psychotic and medically ill patients had an overall poorer response to antidepressants than outpatients. 4) Successful therapeutic augmentation of antidepressant response was reported for methylphenidate, and estrogen replacement. 5) One large study reported hyponatremia commonly developing with SSRIs, although in another report of five elderly volunteers who underwent water-load testing, there was no impairment of water excretion by paroxetine. 6) Four reports of treatment with venlafaxine (com-

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Table 4. Selected Reviews, Chapters Author

Type of Review

Alexopoulos, 1996

Clinical

Alexopoulos, 1998

Literature

Alexopoulos and Salzman 1998

Literature

Amrien et al 1997 Baldwin, 1995

Clinical Retrospective

Barkin et al 2000 Baumann, 1998

Literature Clinical

Bellino et al 2000 Bonner and Howard 1995 Cadieux, 1999

Literature Literature

Casey, 1996 Chiu, 1997

Retrospective Clinical

Cole et al 2000

Literature

DasGupta, 1998 Davis and Matthew 1998 Devane and Pollock 1999 Doraiswamy, 2001 Dunbar, 1995 Emslie and Judge 2000 Finkel, 1996 Flint and Rifat 1997c Flint, 1998e Freudenstein et al 2001 Gareri et al 1998 Gareri et al 2000

Literature Clinical

Clinical

Brief Summary 50% response to TCAs in patients with depression and dementia; enlarged lateral brain ventricles associated with poor response to TCAs. Antidepressants may be effective in the treatment of depression of demented patients. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Mocl ⫽ TCAs, SSRIs; fewer side effects. After treatment, 1⁄4 of patients remained symptom free; 1⁄3 experienced at least 1 relapse, but with further recovery; the remainder have residual symptoms. 10% remain severe and intractable. Emphasis on pharmacokinetics and drug interactions. No age effect on fluox, fluvox metabolism; lower starting doses for cital, parox, sertraline. New antidepressants preferred for dysthymia; need more studies. 18%– 40% true nonresponse to antidepressant treatment.

Clinical Metaanalysis Literature

Emphasizes need for individualized treatment and attention to CP450 interactions. ECT very effective and reasonably safe in very old (⬎75). Usefulness of NT and DMI for severe depression; ECT for psychotic depression. All treatments effective; contraindications to treatment in 38%– 87% of subjects who received a heterocyclic, compared with 4% who received SSRI. Focus on SSRIs, stimulants, and ECT Antidepressants very effective; pharmacokinetic differences lead to different dosing. Optimal doses may not differ from younger patients, but initial doses should be lower. Newer antidepressants recommended for comorbid anxiety and depression. Paroxetine ⫽ or ⬎ amitriptyline, clomipramine, doxepin, mianserin. TCAs ⫽ SSRIs for efficacy; SSRIs ⬎ TCAs for safety.

Clinical Clinical Clinical Literature

SSRIs have similar efficacy and ⬎tolerability than TCAs in 70⫹. Focus on SSRIs: dose, length of treatment, relapse and recurrence rate. All antidepressant classes equally effective, but data inadequate. Inadequate data for treatment of less severe depression.

Clinical Clinical

Newer antidepressants preferred. Focus on age-related changes in kinetics and dynamics; newer antidepressants preferred. All drugs and classes equally efficacious and equally well tolerated. Nefaz clearance reduced in elderly; venlafaxine dosage should be lower in elderly with renal impairment; mocl dosage adjustment unnecessary; more data needed. Cital effective in depression associated with Alzheimer’s. Cital effective in depression associated with Alzheimer’s. Antidepressants (e.g., SSRIs) can induce EPS and Parkinsonism; complex interplay of neurotransmitters, movement, emotion, aging. Role of illness, meds, kinetics; longer duration of treatment necessary. Role of nurses in medication and ECT treatment. Preliminary evidence for use of either TCAs or serotonergic drugs in treatment of major depression during bereavement. Augmenting partial response preferred to switching meds.

Clinical

Gerson et al 1999 Goldberg, 1997

Metaanalysis Literature

Gottfries, 1996 Gottfries, 1997 Govoni et al 2001

Clinical Clinical Literature

Hay et al 1998 Heffern, 2000 Jacobs and Zisook 1998 Kamholz and Mellow 1996 Katona, 1995 Kelly and Zisselman 2000 Kocsis, 1998

Clinical Clinical Literature Clinical Clinical Clinical Clinical

Choice of antidepressant influenced by SE profile. ECT effective, low-risk procedure in medically ill patients. May cause delirium in cognitively impaired patients. Usefulness of antidepressants for dysthyrnia; more data needed.

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Table 4. Continued Author

Type of Review

McCusker et al 1998

Literature

Menting et al 1996 Meyers, 1998

Metaanalysis Literature

Mittmann, 1997 Montgomery, 1998 Mulsant, 2001 Nelson, 1998

Metaanalysis Clinical Literature Literature

Oshima and Higuchi 1999 Oxman, 1996

Literature

Pollock et al 1999 Reynolds et al 1997 Reynolds et al 1998 Robinson et al 1998 Roose and Suthers 1998 Sackeim, 1998 Salzman et al 1995

Clinical Clinical Literature Literature Clinical

Salzman, 1997

Literature

Salzman et al 1998

Literature

Salzman, 1999

Literature

Salzman, 2000

Literature

Schneider et al 1995

Literature

Seidman and Walsh 1999 Simonson, 1997

Clinical

Skerritt et al 1997 Small, 1998 Small and Salzman 1998

Clinical Clinical Literature

Stoudemire, 1997 Sussman, 1998

Literature Literature

Tourigny-Rivard, 1997 VanDerPol et al 1998 Zisook, 1996 Zisook and Downs 1998

Clinical Clinical Clinical Clinical

Clinical

Literature Literature

Retrospective

Brief Summary All antidepressants equally effective; magnitude of treatment effects modest. All antidepressants equally effective. More side effects with TCAs. Combination pharmacotherapy with high doses of neuroleptics or ECT effective. No significant difference in efficacy among antidepressants. SSRIs better tolerated. New treatment algorithm. Review of all antidepressants; relevance of blood levels and dosing emphasized. New antidepressants preferred; ECT for psychotic depression; augmentation has modest efficacy. SSRIs and RIMAs (no anticholinergic effects) produce less cognitive impairment than TCAs. Antidepressant SE increase with age. Antidepressants improve quality of life. Prevention of recurrence uses same dose of therapeutic antidepressant. TCAs and at least 1 SSRI effective treatment of poststroke depression. 50% remission rate with fluox and sert; TCA ⫹ SSRI dropout rate. Efficacy and safety of ECT affirmed. Many poor quality studies; overall no individual antidepressant best for all elderly. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Efficacy and SE rates for any particular medication varies among clinical trials; often depends on drugs being prepared, use of PBO, dose, design of trial. Some men have state-dependent low testosterone; some improve with androgens. Demonstrated therapeutic efficacy; no increased Risk of adverse effects in elderly patients. Clinically important drug interactions with alpraz, triaz, terfen, astemizole, cisapride, digoxin. SSRIs preferred. Newer antidepressants preferred. Emphasis on balancing therapeutic effect against side effects; effect of age on pharmacokinetics and side effects; need for longer treatment periods and gradual dose increases. Biologic markers discussed; long-term follow-up recommended. No preferred class of antidepressants; Parkinsonian patients more sensitive to side effects. Emphasis on newer antidepressants; need more studies. New antidepressants better for community residents. Depression and dysthymia undertreated. Integrate pharmacotherapy with other treatments.

EPS, Extrapyramidal symptoms; DMI, desipramine; ECT, electroconvulsive therapy; NT, nortriptyline; SSRI, selective serotonin reuptake inhibitor; RIMA, reversible inhibitor of monoamine oxidase A; PBO, placebo; SE, side effects; TCA, tricyclic anidepressant; mocl, moclobemide; fluox, fluoxetine; fluvox, fluvoxamine; cital, citalopram; parox, paroxetine; nefaz, nefazodone; alpraz, alprazolam; triaz, triazolam; terfen, terfenazine.

Drug and ECT Treatment of Depression in the Elderly

pared with only one comparative study report) commented on its efficacy in the elderly without increased blood pressure, although headache, nausea, insomnia, and dry mouth were common side effects. There were three reports of the efficacy of reboxetine as well.

Electroconvulsive Therapy in the Elderly (Table 3) Twelve publications reported the effects of ECT. Overall, ECT was found to be efficacious; in four reports it was more therapeutic than antidepressant treatment. ECT was well tolerated by the elderly even in patients older than 80 years. Side effects were noted, especially an increased risk of falls in patients residing in a nursing home. One study mentioned the possibility of developing post-ECT delirium or dementia in older patients although these are not known to be side effects of ECT.

Reviews, Metaanalysees, Selected Chapters Conclusions regarding drug treatment of late-life depression from the review papers and textbook chapters (Table 4) reflect the results of published studies. Taken together, antidepressants were considered at least moderately effective and, depending on dose and patients’ cognitive status and medical condition, reasonably well tolerated in the elderly. Many if not most of the reviews, chapters, and metaanalyses emphasize the equivalent therapeutic efficacy between SSRIs and tricyclics for depressed elderly individuals. This result was supported by nearly two thirds of the 11 comparative studies, but the remaining studies reported superiority of tricyclics. The review papers also strongly supported the use of SSRIs over TCAs because of a more favorable side effect profile, whereas the recent studies suggest only a slight side effect advantage for the SSRIs. Two metaanalyses (Mittmann 1997; Gerson 1999) concluded that all antidepressants are equally efficacious without regard to side effects. Consequently, it appears that clinical recommendations in these reviews favoring SSRIs over tricyclic antidepressants is supported only by the slightly more favorable side effect profile and not by superior efficacy as demonstrated in the 1995–2001 studies included in this review.

Overall Conclusions and Summary It is gratifying to see a marked increase in attention being paid to late-life depression and its treatment. A large number of well-designed studies support the use of drugs and ECT for the safe and effective treatment of depressed elderly individuals. The following overall conclusions can be drawn from this review:

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• The past 6 years of research continue to indicate that all antidepressants are safe when carefully prescribed, and are at least moderately effective. • Despite clinical recommendations favoring SSRIs, these recent studies do not demonstrate superior antidepressant efficacy of one class of antidepressants over another. When ECT was compared with antidepressants it was almost always reported to have superior therapeutic efficacy. • Although SSRIs are commonly recommended as first-choice antidepressants because of a presumed better side effect profile, the difference in their side effects, even when compared with TCAs, is slight. • Nortriptyline was the most frequently studied drug, suggesting a continuing therapeutic role for TCAs in the elderly. SSRIs were also well studied but there continues to be a paucity of comparative clinical trial information on the newer antidepressants. For example, there was only one comparative study each of venlafaxine, bupropion, mirtazapine, and one of nefazodone. • In past studies, depression associated with dementia has been safely treated with SSRIs and tricyclics. These recent studies also demonstrated antidepressant efficacy in patients with dementia. Patients whose depression lifts may also have modest improvement in cognitive function. • Depression is commonly associated with medical illness in the elderly. The three available studies of medically ill depressed elderly patients published in the past 6 years suggest that antidepressants can be used safely in these patients; however, there was only one comparative study (fluoxetine vs. placebo) conducted in a large patient sample, and the therapeutic efficacy was very modest. It is clear that more studies in the population of medically ill depressed elderly individuals are needed. • The aging process is well known to alter the pharmacokinetics of some antidepressant drugs. In these recent studies the observed kinetic changes were less dramatic than previously demonstrated and did not interfere with therapeutic effects. • It is still difficult to draw conclusions regarding the necessity for alterations of dose-range or rate of dose increases in the elderly. For some antidepressants (e.g., nefazodone), age-related pharmacokinetics may cause a prolonged elimination half-life or higher blood levels suggesting the use of lower starting dose. Almost all of the nortriptyline studies adjusted doses according to standard therapeutic plasma range for younger adults, and elderly patients, even those in a nursing home, tolerated this therapeutic range very well. Virtually all of the studies of SSRIs used full

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therapeutic doses. Some, but not all, studies followed the geriatric prescribing maxim “start low go slow,” gradually titrating doses upward. In the nonslow titration studies there were no comments regarding an increased risk of side effects from rapid dose escalation. There is an insufficient number of studies regarding augmentation of antidepressant treatment in nonresponding or partially responding nonpsychotic patients. One study reported successful augmentation of an SSRI with methylphenidate and another described the augmenting effect of estrogen. The efficacy of augmentation with a variety of medications in acute depression therapy was demonstrated in a third study. Patients requiring augmentation showed a high relapse rate when the augmenting medication was discontinued. A fourth study examining the augmenting antidepressant effect of lithium demonstrated a significant reduction of side effects when lithium was withdrawn; although a small number of patients relapsed, the benefit of maintaining elderly patients on lithium did not clearly outweigh the side effects. Although antidepressants were superior to placebo for elderly patients with major depression, it is not clear that they were always more effective than placebo for elderly patients suffering from minor depression or dysthymia. Nonpharmacological treatment was reported to be helpful for nursing home residents with minor depression. It is clear that the risk of relapse or recurrence is high in the elderly population when antidepressants are discontinued. Many of the maintenance treatment studies demonstrated the importance of maintaining older patients on their antidepressant medication. ECT has been considered an effective and safe for the elderly depressed patient, and may be the most rapid and efficacious treatment for the most severely ill patients. The published studies over the past 6 years clearly support its safety as well as efficacy even in very elderly individuals. The mean age of research subjects has increased from approximately 68 years at the last Consensus Conference to 72 years, better reflecting the aging U.S. population. The previous Consensus Conference called for more research in individuals older than 80 years. It is gratifying to see an increase in the number of subjects older than 75 years and older than 80 years in the past 6 years. There are now eight more reports of 80⫹ year-olds. Nevertheless, this “old-old” population is still insufficiently studied compared with elderly individuals younger than 80 years.

• There may be a correlation between response to serotonergic antidepressants and genetic variations in the presynaptic serotonin transporter protein in the elderly. Based on one study, it appears that advanced age does not alter this predictive genetic correlation between transporter polymorphisms and clinical response. • Virtually all studies are still using standardized rating scales created for younger adult populations, primarily the Hamilton Depression and Montgomery Asberg Scales. Although these two scales are considered valid and reliable for the elderly, other scales standardized in younger adults may not be as valid in the elderly. The Mini-Mental Status Examination was also frequently used as an outcome measure in studies of depression. Small changes in this scale raise questions about the validity of study conclusions regarding changes in cognition in depressed elderly subjects. Mood and cognitive scale development with questions specifically designed for the elderly and the very elderly should continue to be a high priority for future research. • Monoamine oxidase inhibitors continue to be demonstrated as a safe and effective medication for depressed elderly individuals in a very small number of studies. More MAOI research is necessary. • Methylphenidate continues to be reported as a safe and effective stimulant in case reports, and in one small comparative trial with chronically ill patients. • More research is needed. Aspects of this work were presented at the conference, “Unmet Needs in Diagnosis and Treatment of Mood Disorders in Late Life,” October 9 –10, 2001 in Washington DC. The conference was sponsored by the National Depressive and Manic-Depressive Association (National DMDA) through unrestricted educational grants provided by Abbott Laboratories, AstraZeneca, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Merck & Co., National Institute of Mental Health, Organon, Pfizer Inc, and Wyeth-Ayerst Laboratories.

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