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 RESEARCH ARTICLE

Treatment of depression associated with age-related macular degeneration: A double-blind, randomized, controlled study

Barbara L. Brody, MPH

Department of Ophthalmology, Department of Family and Preventive Medicine (SDE, Division of Biostatistics), University of California, San Diego, La Jolla, CA, USA

Linda C. Field, MA

Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA

Anne-Catherine Roch-Levecq, PhD

Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA

Christine Y. Moutier, MD

Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

Steven D. Edland, PhD

Department of Family and Preventive Medicine (SDE, Division of Biostatistics), Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA

Stuart I. Brown, MD

Department of Ophthalmolog, University of California, San Diego, La Jolla, CA, USA

BACKGROUND: Depression is frequently found in patients with age-related macular degeneration (AMD). The purpose of this study was to assess the effectiveness of escitalopram in treating major and minor depression in AMD patients.

METHODS: We conducted a crossover, randomized, double-blind, placebo-controlled, 16-week study comparing escitalopram with placebo. Inclusion criteria included reduced vision from AMD and major or minor depression, with a 17-item Hamilton Rating Scale for Depression (HAMD-17) score of ≥10. Participants were randomly assigned to receive either escitalopram or placebo for 8 weeks and then crossed over to the other treatment. The primary outcome was change on the total HAMD-17 score with escitalopram treatment compared with placebo.

RESULTS: We enrolled 16 AMD patients (mean age 79.1), 12 with major depression and 4 with minor depression. Mean HAMD-17 score at enrollment was 16.1 ± 4.2, and mean visual acuity in the better eye was 20/70. During escitalopram treatment, participants showed a significant reduction in HAMD-17 scores compared with placebo treatment (P = .01).

CONCLUSIONS: These findings suggest escitalopram may be an effective treatment for depressive symptoms associated with major or minor depression in AMD patients with vision loss.

KEYWORDS: age-related macular degeneration, major depression, minor depression, escitalopram, crossover trial

ANNALS OF CLINICAL PSYCHIATRY 2011;23(4):277-284

  INTRODUCTION

Depression is common in patients with age-related macular degeneration (AMD).1,2 AMD is the leading cause of permanent vision loss in older adults in the industrial world. It has been described as the epidemic of the baby boomers in the 21st century.3 Today AMD affects 15 to 20 million Americans and 40 to 50 million older persons worldwide. One out of 5 persons age >65 has AMD and 1 out of 3 age >75 has AMD. AMD prevention and treatment options are limited to select cases. Patients with AMD are twice as likely to be depressed as elderly community-dwellers who do not have the disease.2 Depression contributes more to AMD patients’ disability than their vision loss.2,4 Results of a small open-label study suggested the selective serotonin reuptake inhibitor (SSRI) sertraline might be a safe and effective treatment for depression in patients with AMD.5

Depression often co-occurs with medical conditions—such as stroke, cancer, myocardial infarction, Parkinson’s disease,6 and congestive heart failure7,8—but it remains under-recognized and under-treated in medical patients.9 Depression accounts for poor quality-of-life ratings and has a negative impact on recovery from illness.10 It may increase mortality risk in certain medical conditions, such as coronary heart disease11 and rheumatoid arthritis.12 Evidence is growing that antidepressant treatment is equally effective for major depressive disorder, whether or not accompanied by chronic medical comorbidity.13,14

The effectiveness of the SSRI escitalopram has not been studied in elderly patients with depression and AMD, nor has a randomized, double-blind investigation of SSRIs been conducted in this population. The primary intent of this study was to determine if depressed AMD patients would show a significant decrease in depressive symptoms with escitalopram treatment compared with placebo in a double-blind, randomized, controlled trial.

  METHODS

Study population and participant flow

We recruited community volunteers through physician offices, the media, an AMD registry, health fairs, senior centers, and retirement communities. Eighteen individuals met inclusion criteria and were enrolled. The study psychiatrist discontinued 2 participants for personal reasons within 1 week of screening, and their data were excluded from analyses. Their demographic, macular degeneration, or depression rating characteristics did not differ from those of the 16 individuals who completed the study.

Inclusion criteria were diagnosis of AMD; visual acuity 20/40 or worse in the better eye; no other unstable eye disease; diagnosis of depressive disorder (major or minor depression) by Structured Clinical Interview for DSM-IV (SCID-IV)15; 17-item Hamilton Rating Scale for Depression (HAMD-17)16,17 score of ≥10; no cognitive impairment by the Orientation-Memory-Concentration Test (OMC)18; no hearing problems significant enough to impede assessment; no psychotic disorder; no substance abuse; no history of known allergy to the study drug; no severe or acute medical illness for 6 months; no history of suicidal or violent behavior; no recent use (2 weeks) of any psychotropic medication; and no initiation of psychotherapy within 3 months before study entry.

Design and procedures

The University of California San Diego Human Research Protections Program approved the protocol for this study (#090013) in December 2002. We obtained informed consent before screening and enrolling participants in the study. This was a 16-week AB-BA crossover, randomized, double-blind, placebo-controlled study to measure the efficacy of escitalopram in AMD patients with major or minor depression. The study took place in a university department of ophthalmology outpatient setting and was conducted in collaboration with the university’s department of psychiatry. Data came from interviews performed by a trained research associate and study psychiatrist using the measures described below. Masking of the study medications was performed under the direction of a research pharmacist. Study assignment was kept in a locked location and was known only by a research associate not otherwise involved in the study, with provision for the exception in the event of a safety concern. Participants received the first arm of treatment for 8 weeks and then were directly crossed over. Assessments were performed at baseline, 8 weeks, and 16 weeks.

Baseline assessment

Individuals who met inclusion criteria were enrolled and randomly assigned to receive escitalopram during the first 8-week period followed by placebo during the second 8-week period (the AB group) or placebo during the first period followed by escitalopram during the second period (the BA group). Baseline assessments were performed using the measures below.

8-week assessment and crossover

Participants were comprehensively evaluated again at 8 weeks with the same measures used at baseline. After being assessed by the study psychiatrist, they were crossed over to the other study treatment.

16-week assessment and exit

Participants were comprehensively evaluated at 16 weeks with the same battery used at baseline and at crossover assessments. The study psychiatrist referred those requiring additional psychiatric care and arranged follow-up dispositions when the protocol was completed.

Monitoring

At weeks 2 and 10 a research associate met with participants to monitor compliance. The study psychiatrist monitored response and any adverse effects. At weeks 5 and 13 a research associate telephoned participants and used a standard questionnaire to monitor and evaluate compliance and adverse effects.

Safety measures

Standard safety procedures were in place. Participants were given a 24-hour contact phone number to reach the research associate and study physician if they had questions about the medication or were experiencing side effects or adverse reactions. All side effects or adverse reactions were evaluated, and the study psychiatrist was available to provide treatment, make referrals, and/or discontinue study medication as needed. Participants were warned against using alcohol or other drugs in combination with the study medication and about the risks of driving. To assure confidentiality of data, records were kept in double-locked files, participants were assigned project numbers, and no personal identifiers were used in analyzing data or reporting the findings.

Dosing

All participants began with a 10 mg/d dose of escitalopram/placebo, with the option to titrate down to 5 mg/d for tolerability.19

Measures

The primary outcome measure was change from start to end of each 8-week period on the HAMD-17 total score. The HAMD-17 is the research standard to assess depression severity and response to therapy in clinical investigations. It is based on the clinician’s interview with the patient and probes symptoms such as depressed mood, guilty feelings, suicide, sleep disturbances, anxiety levels, and weight loss. Possible total scores range from 0 to 54.

Secondary outcome measures included comparative change from start to end of each 8-week period in HAMD-17 response rates—defined as ≥50% reduction in total score—and in HAMD-17 remission rates (defined as total score <7). Other secondary measures were:

Hamilton Rating Scale for Anxiety (HAM-A)20 total score. The HAM-A is a validated instrument with 14 items scored on a 5-point scale, 0 (not present) to 4 (severe), to give a total score of 0 to 56. This widely used scale measures anxiety severity based on parameters including mood, tension, fears, and somatic complaints. It is useful mainly for assessing an individual’s response to therapy or drug treatment.

The 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ)21 is widely used to assess impairment in vision-related functioning. Scores range from 1 to 100, with higher scores indicating better functioning. An overall summary scale was created using the average of the 12 subscales.

The Macular Degeneration Self-Efficacy Scale (AMD-SEQ)22 is a 13-item self-report used to evaluate expectations for handling defined situations related to AMD. Scores range from 1 to 100, with higher scores indicating greater self-efficacy.

Self-rated quality of life22 is a single question using a rating scale of 1 to 100, with higher scores indicating better quality of life.

Measures of clinical and demographic characteristics

Health and Impact Questionnaire.22 Participants provided information about their general health and the impact of macular degeneration on their lives using the Health and Impact Questionnaire. This medical history includes questions on current medications, living arrangements, and education.

Visual acuity. Visual acuity of the better eye and worse eye were obtained using the Snellen chart. Snellen ratings were then converted to the logarithm of the minimum angle of resolution (LogMAR) scale, on which an increase of 1 point represents a 10-fold drop in vision on the Snellen scale. Whereas 20/20 refers to normal vision and 20/200 to legal blindness on the Snellen scale, 0.0 represents normal vision and 1.0, legal blindness on the LogMAR scale.23

Statistical analysis

Descriptive statistics were used to characterize the sample data at baseline. Continuous variables were compared between the AB and BA groups using 2-sample t tests or, if normality and homogeneity of variance assumptions were not met, Mann-Whitney U tests.

The primary study hypothesis was that escitalopram would be effective in improving depressive symptoms as measured by the primary outcome measure: total score on the HAMD-17, compared with placebo. Treatment effects for this 2-treatment by 2-period crossover study were tested using a repeated measures analysis of variance (ANOVA), with sequence (drug then placebo; placebo then drug) as a between-subjects factor and treatment (drug, placebo) and period (baseline, after first treatment, after second treatment) as within-subject factors.24 This statistical method detects effects of the drug as a sequence-period interaction and any carryover effects as a sequence main effect. Descriptive odds ratios (ORs) were used to compare discrete responses across treatments.

Analysis of treatment effects was performed with the R statistical programming language25 using the ANOVA function aov. All other descriptive statistics were calculated using Statistica for Windows, version 9.0 (Statsoft, Tulsa, OK). Statistics are reported with 95% confidence intervals (CI), and the significance level for hypothesis testing was set at P < .05.

  RESULTS

Patient characteristics at baseline

As shown in (TABLE 1), the 2 groups were similar at baseline with regard to demographic and clinical factors. Mean age of the 16 participants was 79.1; 63% were female; mean visual acuity in the best eye was 20/70. Nine reported previous antidepressant use; 8 had received antidepressant prescriptions from their primary care physicians and 1 from a mental health professional.


TABLE 1

Demographic, socioeconomic, and clinical characteristics of depressed AMD participants

Characteristics All
(N = 16)
Escitalopram first (n = 7) Placebo first (n = 9) P values
Age, y
Mean (SD)
Range
79.1 (4.4)
67 to 86
78.7 (6.6)
67 to 86
79.8 (2.3)
76.83
.79
Sex
Female
Male
10 (62.5%)
6 (37.5%)
3 (42.9%)
4 (57.1%)
8 (88.9%)
1 (11.1%)
.11
Years of education
Mean (SD)
Range
15.5 (2.9)
12 to 22
15.6 (2.1)
12 to 22
14.8 (3.7)
12 to 22
.43
Marital status
Married
Single
7 (43.8%)
9 (56.2%)
2 (28.6%)
5 (71.4%)
4 (44.4%)
5 (55.6%)
.63
Living arrangement
Alone
Living with other(s)
8 (50%)
8 (50%)
3 (42.9%)
4 (57.1%)
5 (55.6%)
4 (44.4%)
1.00
Visual acuity
Mean best LogMAR (SD)
Range
Mean worst LogMAR (SD)
Range
0.54 (0.31)
0.30 to 1.30
1.21 (0.67)
0.50 to 2.60
0.64 (0.42)
0.30 to 1.30
1.07 (0.64)
0.50 to 2.30
0.47 (0.17)
0.30 to 0.80
1.31 (0.71)
0.50 to 2.60

.54

.52
HAMD-17
Mean (SD)
Range
16.06 (4.20)
10 to 23
17.10 (4.45)
10 to 23
15.22 (4.02)
11 to 23
.38
HAM-A
Mean (SD)
Range
13.63 (5.20)
3 to 24
14.30 (7.65)
3 to 24
13.11 (2.47)
3 to 24
.69
NEI-VFQ total score
Mean (SD)
57.74 (8.47)
44.7 to 70.2
55.64 (7.87)
46.4 to 66.3
59.38 (9.01)
44.6 to 70.2
.35
AMD-SEQ total score
Mean (SD)
Range
67.96 (17.41)
34.4 to 92.9
68.81 (19.95)
39.6 to 91.5
67.29 (16.40)
34.4 to 92.9
.83
Self-rated quality of life total score
Mean (SD)
Range
36.88 (14.82)
15.0 to 60.0
31.43 (9.88)
20.0 to 50.0
41.11 (17.10)
15.0 to 60.0
.30
Number of patients with history of antidepressant use 9/16 4/7 5/9 1.00
AMD: age-related macular degeneration; AMD-SEQ: Macular Degeneration Self-Efficacy Scale; HAM-A: Hamilton Rating Scale for Anxiety; HAMD-17: 17-item Hamilton Rating Scale for Depression; LogMAR: logarithm of the minimum angle of resolution; NEI-VFQ: 25-item National Eye Institute Visual Functioning Questionnaire.
Efficacy analyses

Primary outcome. Individual scores on HAMD-17 at baseline, crossover, and exit are compared in the FIGURE. Mean response to escitalopram was >7.6 points than response to placebo in the group that received active treatment first (AB), and >6.0 points in the group that received placebo first (BA) (TABLE 2). Overall treatment effect of escitalopram was significantly greater than the effect of placebo (sequence by period F statistic = 5.40, P = .011). A statistically significant sequence effect suggests carryover effects in the trial (sequence effect F statistic = 4.92, P = .032).

Net decline in mean HAMD-17 score was 4.7 points in the AB group and 11.9 in the BA group. Those receiving active treatment during phase 1 improved during this period and regressed when active treatment was removed. Those receiving placebo first improved modestly during period 1, then further improved when they received active treatment during period 2 (TABLE 2).

Restricting the primary analysis to participants with major depression had essentially no effect on the analysis, increasing the statistical significance of the overall treatment effect only modestly (P value decreasing from P = .011 when the 4 patients with minor depression were included to P = .010 when the analysis was restricted to the 12 patients with major depression).

Secondary outcomes. Participants’ HAMD-17 scores were more likely to decline by ≥50% while treated with escitalopram than with placebo (10 of 16 while on escitalopram vs 2 of 16 while on placebo, OR = 11.67, 95% CI = (1.94 to 70.2), P = .009). Participants also were more likely to experience remission (HAMD-17 score <7) on escitalopram (9 of 16 while on escitalopram vs 1 of 16 on placebo, OR = 19.3, 95% CI = [2.03 to 183.42], P = .006). This difference remained when only those diagnosed with major depression at baseline were considered (7 of 12 experiencing remission vs 1 of 11, OR = 15.40, 95% CI = [1.50 to 161.0], P = .03). For those with minor depression, 3 of 4 experienced remission while on escitalopram compared with 1 of 4 while on placebo.

On HAM-A, in terms of anxiety severity, mean response to escitalopram was >7.1 points than response to placebo in the AB group, and >3.7 points in the BA group (TABLE 2). Overall treatment effect of escitalopram was significantly greater than the effect of placebo (sequence by period F statistic = 5.11, P = .011). Carryover effects were not evident on the secondary HAM-A outcome (sequence effect F statistic = 2.00, P = .16).

In post hoc analyses of self-reported quality-of-life ratings, patients receiving escitalopram tended to report greater improvement in overall quality of life compared with placebo, P = .12.

No serious adverse events occurred. One participant’s escitalopram dose was reduced to 5 mg after 1 week because of insomnia and GI upset; these side effects resolved, and the participant completed the study with no adverse effects. Other minor adverse events included loose stool, falling down a step, transient sweating, and sleepiness, all of which were brief and resolved spontaneously.

FIGURE: Individual scores at baseline, crossover, and exit on the HAMD-17 scale for participants given escitalopram first (AB) and placebo first (BA) and diagnosed with major and minor depressiona

aDiagnoses of major and minor depression were determined by the Structured Clinical Interview for DSM-IV (SCID-IV).
HAMD-17: 17-item Hamilton Rating Scale for Depression.


TABLE 2

Mean change (SD) in outcome measures for groups AB and BA by 8-week period

Order Period 1 Period 2 Difference across periodsc Treatment effect (P value)
HAMD-17
E 1st: ABa
P 1st: BAb

AB: –6.14 (5.10)
BA: 1.43 (5.62)

BA: –2.89 (4.50)
AB: –8.89 (5.62)

–7.57 (10.33)
6.00 (9.31)
.01
HAM-A
E 1st: AB
P 1st: BA

AB: –4.00 (7.80)
BA: –3.22 (3.50)

BA: 3.14 (7.40)
AB: –6.89 (4.00)

–7.14 (14.80)
3.67 (6.80)
.01
Visual acuity in LogMAR
Best eye
E 1st: AB
P 1st: BA

AB: .07 (.12)
BA: –.02 (.16)

BA: –.06 (.07)
AB: .01 (.15)

.13 (.19)
.03 (.31)


.89
Visual acuity in LogMAR
Worst eye
E 1st: AB
P 1st: BA

AB: .08 (.14)
BA: –.01 (.14)

BA: –.06 (.11)
AB: .01 (.10)

.14 (.19)
.00 (.19)


.98
NEI-VFQ
E 1st: AB
P 1st: BA

AB: –.83 (4.88)
BA: –1.14 (7.65)

BA: –2.56 (4.75)
AB: 1.11 (4.56)

1.73 (6.28)
2.26 (11.00)
.83
Self-efficacy
E 1st: AB
P 1st: BA

AB: –2.01 (15.75)
BA: 3.97 (11.18)

BA: –2.71 (14.46)
AB: –4.24 (12.43)

0.70 (27.98)
–8.21 (20.90)

.83
Self-rated quality of life
E 1st: AB
P 1st: BA

AB: 14.29 (13.36)
BA: 5.56 (19.28)

BA: –9.86 (19.89)
AB: 15.00 (17.14)

24.14 (25.64)
9.44 (34.04)

.12
aE 1st: AB=Escitalopram first.
bP 1st: BA=Placebo first.
cFor measures where a lower score indicates improvement (such as HAMD-17, HAM-A), a negative difference across periods in the AB group and a positive difference across periods in the BA group indicates a greater improvement under escitalopram compared with placebo.
HAM-A: Hamilton Rating Scale for Anxiety; HAMD-17: 17-item Hamilton Rating Scale for Depression; LogMAR: logarithm of the minimum angle of resolution; NEI-VFQ: 25-item National Eye Institute Visual Functioning Questionnaire.

  DISCUSSION

Escitalopram therapy had a significant effect on major and minor depression symptoms in individuals with AMD in this 16-week double-blind, randomized, controlled, crossover study. Depressive symptom severity decreased significantly, as measured by HAMD-17 scores after 8 weeks of active treatment vs 8 weeks of placebo. Escitalopram treatment also was more likely to result in response—≥50% reduction in HAMD-17 score—and more likely to result in remission (HAMD-17 score <7).

Although the 4 participants with AMD and minor depression comprised a small cohort, the improvement in their HAMD-17 scores with active drug compared with placebo may be an important finding. Given evidence that minor and subsyndromal symptoms affect depression’s prognosis and course26,27 and antidepressant treatment effect may correlate with severity of depression,28 our finding of significant improvement with antidepressant treatment in individuals with minor depression is noteworthy. A significant treatment effect on anxiety as measured by HAM-A is consistent with the effects of SSRI treatment.

No significant changes were seen on the other secondary measures of function and self-efficacy. A longer course of treatment or additional follow-up may have been needed for these measures to show significant change. Alternately, escitalopram’s effects on these measures might have been enhanced with concomitant or subsequent cognitive-behavioral therapy, which our group has used in treating depression in persons with AMD.22,29,30

This study was limited to AMD patients with permanently reduced vision who had major or minor depression. We view the symptoms of the study participants as a depressive syndrome that has developed concurrently with AMD. Persons with recurrent depressive disorders are vulnerable to relapse and chronicity, especially with the onset of new medical illness.

A limitation of the crossover design is the possibility of carryover effects or order of treatment effects. Given the AB-BA crossover design of our trial, we have considered the possibility that SSRI discontinuation symptoms in the group exposed to escitalopram during period 1 persisted and affected the HAMD-17 scores at the end of period 2. Persistent discontinuation syndrome symptoms can occur with SSRI discontinuation but were not observed in adverse event monitoring of this trial or reported by participants, all of whom had 24-hour telephone contact and were encouraged to report any adverse events or questions.

An alternate explanation for the crossover effect observed in our trial is that the improvements in mood during active treatment of the AB group washed out when active treatment was removed, whereas the improvements in mood acquired during the placebo period of the BA group persisted when active treatment was initiated. We note that the best, unbiased estimate of placebo effect is the BA group response to placebo during period 1, where an improvement of 2.9 points was observed in 8 weeks. This is less than one-half the improvement observed under active treatment during period 1 in the AB group (6.1 points in 8 weeks) and less than one-third of the improvement observed during period 2 in the BA group (8.9 points in 8 weeks). Hence, even when we ignore the AB group period 2 data, where patients regressed during placebo treatment, the trial data strongly argue in favor of a positive effect of escitalopram compared with placebo.

  CONCLUSIONS

Although the results were encouraging, the small sample size prevents us from definitively concluding that these findings apply in general to depressed AMD patients with vision loss. Effectively treating depression concomitant with other medical illnesses has been shown to improve patients’ quality of life and function. Further research with a larger sample using a randomized, placebo-controlled design is warranted to confirm our findings regarding the efficacy of antidepressant treatment for individuals with impaired vision related to AMD.

AUTHORS’ CONTRIBUTIONS: Ms. Brody participated in the study conception and design, analysis, and interpretation of data, and drafting and revising the paper. Ms. Field participated in analysis and interpretation of data, and drafting and revising the paper. Dr. Roch-Levecq participated in analysis and interpretation of data, and drafting and revising the paper. Dr. Moutier participated in study conception and design, analysis, and interpretation of data, and drafting and revising the paper. Dr. Edland participated in analysis and interpretation of data and revising the paper. Dr. Brown participated in study conception and design, analysis, and interpretation of data, and drafting and revising the paper.

ACKNOWLEDGEMENTS: The study was funded in part by an investigator-initiated grant from Forest Laboratories, Inc., and by Shiley Awards in Health Education and the Arts. Forest Laboratories also supplied the escitalopram and placebo. The funding sources did not play any part in the study design; the collection, analysis, or interpretation of data; or the writing of this report.

DISCLOSURE: The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: Christine Y. Moutier, MD, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92161 USA, E-MAIL: cmoutier@ucsd.edu