Huang 2014

Accepted Manuscript

A systematic review and meta-analysis of psychotherapy for late-life depression

Alice X. Huang, MD, MS Kevin Delucchi, PhD Laura B. Dunn, MD J. Craig Nelson,MD

PII: S1064-7481(14)00121-3

DOI: 10.1016/j.jagp.2014.04.003

Reference: AMGP 367

To appear in: The American Journal of Geriatric Psychiatry

Received Date: 10 January 2014

Revised Date: 27 March 2014

Accepted Date: 14 April 2014

Please cite this article as: A.X. Huang, K. Delucchi, L.B. Dunn, J.C. Nelson, A systematic review andmeta-analysis of psychotherapy for late-life depression, The American Journal of Geriatric Psychiatry(2014), doi: 10.1016/j.jagp.2014.04.003.

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http://dx.doi.org/10.1016/j.jagp.2014.04.003

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Manuscript 4210 words Title: A systematic review and meta-analysis of psychotherapy for late-life depression Byline: Alice X. Huang, MD, MS; Kevin Delucchi, PhD; Laura B. Dunn, MD; J. Craig Nelson, MD Authors: Alice X. Huang, MD, UCSF Department of Psychiatry and Langley Porter Psychiatric Institute; Kevin Delucchi, PhD, UCSF Department of Psychiatry and Langley Porter Psychiatric Institute; Laura B. Dunn, MD, UCSF Department of Psychiatry, Langley Porter Psychiatric Institute, and UCSF Helen Diller Family Comprehensive Cancer Center; J. Craig Nelson, MD, UCSF Department of Psychiatry and Langley Porter Psychiatric Institute Correspondence: J. Craig Nelson, MD 401 Parnassus Avenue, Box 0984 San Francisco CA 94143-0984 Phone: (415)-476-7405 Fax: Email: [email protected]

Previous Presentations: 1. American Psychiatric Association Annual Meeting 2013, San Francisco. May 20, 2013 2. American Association for Geriatric Psychiatry Annual Meeting 2013, Los Angeles. March

14, 2013

Disclosures and Acknowledgements: Alice X. Huang reports no competing interests. Kevin Delucchi reports no competing interests. Laura B. Dunn reports no competing interests. During the past 12 months J. Craig Nelson, M.D. has served as a consultant, adviser, or speaker for, received research support or travel support from, or participated in CME for Bristol-Myers Squibb, Cenestra Health, Corcept, Eli Lilly, Eli Lilly Global, Forest, Health Resources and Services Administration, , Lundbeck, Mylan/Dey Pharma, NIMH, Otsuka USA, Otsuka Asia, Pfizer, Shire, and Sunovion;, and he owns stock in Atossa. Grant Support: for this study was provided by the UCSF Epstein Endowment.

Keywords: geriatric, psychotherapy, late-life depression, meta-analysis

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FINAL MANUSCRIPT WITH TRACKED CHANGES

Abstract

Objectives: To determine the efficacy of psychotherapy in late-life depression and to determine

the effect of the type of control group on the magnitude of psychotherapy effects

Design: A systematic review and meta-analysis of randomized controlled psychotherapy trials

for late-life depression

Setting: Outpatient clinics or in subjects’ home

Participants: Subjects ≥ 55 years of age with acute-phase depressive disorder

Measurements: Change in depressive symptoms was measured with validated scales.

Standardized mean differences (SMD) were calculated for each therapy-control contrast, as

meta-analytic summaries for contrasts using a similar control, and for all contrasts combined.

Results: The search identified 27 trials with 37 therapy-control contrasts and 2,245 subjects.

Trials utilized 5 types of control groups (waitlist, treatment-as-usual, attention, supportive

therapy, placebo). In the combined contrasts, psychotherapy was effective (SMD=0.73; 95% CI

0.51, 0.95; z=6.42, p<.00001). The SMD varied widely (from 0.05 to 1.36) and significantly

(χ2=35.67, df=4, p<.00001) between subgroups by type of control. In 5 trials that compared

psychotherapy with supportive therapy, the SMD was 0.39 (95% CI 0.16, 0.61; z=3.37,

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p<0.0007; I2=0%). The SMD was 0.11 within the waitlist controls and 1.10 within the supportive

therapy subgroup.

Conclusions: Psychotherapy is effective for late-life depression, but the magnitude of the effect

varies widely with the type of control group. Supportive therapy appears to best control for the

non-specific elements of psychotherapy and is associated with considerable change itself, but

few trials have employed it as a control.

Keywords: geriatric, late-life depression, psychotherapy, meta-analysis

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Objective

Depression is a common disorder in older adults that reduces quality of life and increases

disability, risk of suicide, morbidity, and mortality (1). Usual treatments include antidepressants,

psychotherapy, or a combination. Antidepressants are effective, but effects are modest (2) and

their use may be complicated by medical comorbidities, drug-drug interactions, and increased

vulnerability of elders to side effects. Finally, some patients prefer psychotherapy.

In the past decade, several reviews have examined the evidence for psychotherapies

targeting late-life depression (3-7) and have concluded that psychotherapy is effective (3-6) and

that it has “moderate to large effects” (3,5,6). Conclusions about the effectiveness of

psychotherapy may be premature, however, without adequate consideration of the type of

controls employed.

Unlike antidepressant trials, in which a placebo control remains the gold standard, types

of control groups utilized in psychotherapy trials vary widely. In psychotherapy trials for late-life

depression, examination of the effects of these controls on outcomes has been limited. Cuijpers

et al. (5) found no effect of the type of control condition on the magnitude of the treatment-

control difference; however, in that study, 11 of the 18 trials utilized a waitlist control, and the

study did not explicitly examine supportive therapy, attention, and placebo controls.

The effects of different types of control groups have been examined in mixed-age

samples (8,9). For example, Baskin et al. (8) demonstrated that smaller effect sizes result when

psychotherapy is compared to structurally equivalent controls (e.g. in number and duration of

sessions, format of therapeutic interaction) than when compared to structurally dissimilar

controls. Supportive therapy may best control for the non-specific factors common to all

psychotherapies (attention, education, reassurance, monitoring symptoms) (10). These factors

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must be accounted for if trials are to provide strong evidence for the specific elements of

psychotherapies.

We performed a systematic search of randomized controlled trials (RCTs) of

psychotherapy in late life depression with the following goals: 1) to examine the effects of all

types of control groups employed in late-life depression trials on the magnitude of the therapy-

control differences; 2) to specifically determine the magnitude of treatment-control differences

when supportive therapy is the control and determine which psychotherapies have been

compared with supportive therapy; and 3) to systematically review all appropriate trials

published, including those published since the last review. We hypothesized that psychotherapy

would yield large effects when compared to waitlist, attention, or treatment-as-usual (TAU)

controls, but that the effects would be smaller when compared with supportive therapy. We

intentionally began our review with an inclusive approach and performed sensitivity analyses to

determine the effects of restrictive criteria. Finally, we were interested in the magnitude of

change that occurs within different controls, particularly waitlist controls and supportive

psychotherapy. As an exploratory analysis, we examined the effect size of change that occurred

within the different control groups.

Method

Search Strategy

We searched electronic databases PubMed (MESH and text), PsycInfo (title, keywords

and text), and Cochrane Central Register of Controlled Trials (MESH, keywords, title, abstract)

on May 11, 2012. We used terms the intervention (“psychotherapy,” “counseling,” “counseling,”

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“therapy”), the older adult population (“aged,” “aging,” “elder,” “elderly,” “geriatric,” “late life,”

“later life,” “old,” “older”), and depression symptomatology (“depressed,” “depression,”

“depressive disorder”). We limited the search to published, English language, and randomized

controlled trials. We also examined recent reviews and a web database of psychotherapy trials

(11). Finally, we cross-referenced the search arms and removed duplicates.

Definition of Psychotherapy and Type of Control

We defined “psychotherapy” using a modification of a definition by Baskin et al (8).

Psychotherapy must have been delivered face-to-face by a trained therapist and the interaction

with the patient was the vehicle through which the therapeutic components were delivered. It

must have included two of the following: (a) treatment based on psychological principles, (b)

treatment offered to the psychological community (e.g. a manual was available), and (c)

treatment with specific components intended to be therapeutic. We excluded interventions

designed as adjuncts to pharmacotherapy or treatments that were not stand-alone treatments.

Because several bibliotherapy trials were performed in late-life depression, we included these

trials even though they were not administered face-to-face. We then performed a sensitivity

analysis to determine the effect of their inclusion.

Control groups described as “waitlist,” “delayed treatment,” or “no treatment” were

categorized as waitlist controls. “Treatment-as-usual” or “care-as-usual” controls were grouped

together. Control groups that controlled for time spent with the therapist while avoiding

therapeutic interventions were categorized as attention controls. Control groups that met

regularly and provided education and support were categorized as supportive therapy. In studies

comparing psychotherapy, antidepressants, and placebo, psychotherapy was contrasted with

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placebo controls. Two authors (AXH, JCN) reached a consensus about the designation of the

control group.

Inclusion/Exclusion Criteria

We included acute-phase randomized controlled trials of psychotherapy published in

peer-reviewed journals from the inception of the PubMed, PsycInfo, and Cochrane Central

Register of Controlled Trials databases and that specified a minimum age of 55 years.

Depression was diagnosed using either DSM III or IV criteria or required a minimum score on a

depression rating scale. Included studies assessed outcomes with a validated symptom scale. We

excluded maintenance and prevention trials, interventions not meeting our psychotherapy

definition, trials with no depression criteria, trials that included patients with dementia, and trials

limited to one medical disease (e.g. Parkinson’s disease, stroke). We excluded trials using the

abstract when possible. When the abstract was insufficient, two authors (AXH, JCN) examined

the full article and reached consensus regarding inclusion.

Data Extraction

Data extracted included minimum and mean age of the subjects, sex, number of subjects

randomized, number of dropouts, number of subjects analyzed, number of treatment arms, type

of treatment and controls, duration of the trial, number of sessions, type of analysis (intention-to-

treat (ITT) versus completer) and whether clinician ratings were blind to treatment assignment. If

duration differed in the control and treatment arms, outcome was compared at the end of the

controlled period. If critical values for the analysis were not reported, we attempted to obtain

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them from the authors. Data were extracted by one of the authors (JCN) and independently

checked by another author (LBD).

Quality Assessment

We used the 25-item psychotherapy quality rating scale (RCT-PQRS) developed by the

American Psychiatric Association’s Committee on Research on Psychiatric Treatments to assess

the quality of the trials (12).

Statistical Analyses

Because all trials reported change on depression scales while a minority reported

response and remission rates, change scores were employed to assess outcome using

standardized mean difference scores (SMDs) as a measure of effect size. The SMD is the

difference between the mean change scores of the treatment and control groups divided by the

standard deviation of the difference. SMDs are weighted by the sample size in the meta-analysis.

If change scores and their standard deviations (SDs) were not reported, we calculated change

scores subtracting the endpoint score from baseline score. We calculated the SD of the change

score using the following formula from the Cochrane Handbook (13) that accounts for the

correlation between baseline and endpoint ratings. We estimated this correlation (r=0.2,

df=4137) using individual patient data (N=4139) from a prior late-life depression study (14).

______________________________________________ SDchange = √ SD2

baseline + SD2endpoint - (2 x corr x SDbaseline x SDendpoint )

If endpoint scores from the last visit were not reported for the ITT sample, we used the observed

final visit score in completers. If SDs of mean values were not reported and could not be

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calculated, we attempted to obtain them from the authors. If we were unable to obtain them, SD

values were imputed (for two contrasts) using other trials with that scale.

Because different rating scales were employed and several trials included more than one

scale, we used a fixed algorithm based on frequency to determine which scale to include

(Hamilton Rating Scale for Depression [HRSD] > Beck Depression Inventory [BDI] > Geriatric

Depression Scale [GDS] > other scale). The use of different scales to assess change was partially

mitigated by the use of standardized scores. A sensitivity analysis also was performed limiting

the trials to those using the HRSD.

Effects were expressed as SMDs with the 95% confidence intervals (CIs), z-score, and p-

values. Effects were calculated for each treatment-control contrast, for the trials grouped by type

of control condition, and as a meta-analytic summary for all treatments combined using a

random effects model. In studies with more than one active or control arm, we entered the full

sample for each treatment and control contrast. Heterogeneity was determined for each subset of

trials grouped by type of control and for the summary meta-analysis and expressed as χ2 and I2-

statistics. Review Manager version 5.25 (The Cochrane Collaboration, Oxford, England) was

used for statistical calculations.

Sensitivity analyses were performed to test if limiting trials to those that used the same

rating scale (the HRSD) differed from results using various scales and to determine if results

differed if we adjusted the size of the treatment or control group for those included in more than

one contrast. Because we used an inclusive approach, we examined if results differed had we

restricted trials to those with a minimum age of 60 years, to only subjects with MDD, to those

that performed only face-to-face psychotherapy or individual therapy. In an exploratory analysis,

we examined the correlations of the SMDs with mean age of the sample, duration of the trial,

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number of sessions, baseline depression severity, sample size, publication year, and study

quality. To estimate severity, scale totals were converted to 17-item HRSD scores (see Text,

Supplement Digital Content 1, which describes the conversion). To assess publication bias, we

created a funnel plot, performed an Egger analysis (15), and determined the association of

sample size with the SMD. To assess recent trends in trial methodology we examined the

association of year of publication with the factors described above.

We examined the standardized mean difference (baseline-endpoint depression

scores/SDchange) within different control subgroups correcting for the association of repeated

measures.

Results

Characteristics of Included Studies

Our search yielded 2706 potential articles (Figure 1). Review of key articles, reviews, and

the online psychotherapy database produced another 64 articles. We excluded 2628 articles

based on abstract, and reviewed the remaining 142 full articles. There were 13 articles cited in

other reviews that were excluded because they did not meet our inclusion criteria (see Text,

Supplemental Digital Content 2, which describes these excluded trials ).

A total of 27 trials conducted between 1981 and 2011 were selected (Table 1) (16-42).

Four trials were included after authors supplied additional data (23,38,41,42). Since the last

meta-analysis of late-life depression (7), 8 trials were published (18,20,27,28,30,36,41,42).

Outcome data were reported for 2,245 subjects. The types of psychotherapy included were:

cognitive behavioral therapy, cognitive therapy, behavioral therapy, problem-solving therapy

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(PST), interpersonal therapy, brief dynamic therapy, bibliotherapy, reminiscence therapy, and a

“Coping with Depression” course (26). Therapies were conducted in individual or group settings.

The types of control groups were: waitlist, TAU, attention, supportive therapy, and

placebo. Trial duration ranged from 4 to 26 weeks (median 7 weeks), with 4 to 12 psychotherapy

sessions (median 8 sessions). Reporting of treatment received in the TAU condition was variable

and ranged from no treatment to protocol-guided pharmacotherapy. Studies with supportive

therapy, attention, and placebo controls matched the number of sessions to the psychotherapy

intervention. Most samples were outpatient, though 4 trials involved home-based interventions

(24,25,27,28). Several trials had multiple treatment or control groups resulting in a total of 37

treatment-control contrasts. Trial characteristics are shown in Table 1.

Quality Assessment

Study quality was variable ranging from “exceptionally good” to “very poor” on the

RCT-PQRS. Numeric total scores ranged from 18 to 43 (mean 27.4; possible range 0-48). Total

quality scores, which were weighted for sample size, were highly correlated with year of

publication (r=0.68, df=25, p<.001). Of the 27 trials, 10 used an intention-to-treat analysis and 7

defined the primary outcome. All trials randomized subjects, but randomization was modified in

some, especially group treatment studies. In 11 trials, raters were blind to treatment assignment.

In 8 trials with clinician ratings, blinding of raters was not reported. In the 8 remaining trials, the

primary scale was a self-report.

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Meta-analysis Results

In all contrasts combined, treatment was more effective than control and the standardized

mean difference (SMD) for psychotherapy versus control was 0.73 (95% CI [0.51, 0.95], Z=6.42,

p<.00001) (Figure 2). There was significant heterogeneity for all contrasts combined (χ2=226.54,

df=36, p<.00001, I2=84%).

The test for subgroup differences, grouped by type of control, was significant (χ2=35.67,

df=4, p<.00001). The SMDs for the subgroups ranged from 0.05 to 1.36. Heterogeneity was

substantial in the subgroups using TAU and attention controls, moderate in the waitlist controls,

and not significant for supportive therapy and placebo controlled trials (Table 2).

Sensitivity Analyses

We corrected for duplicate entries by dividing the number of subjects by the number of

entries and found that the overall SMD was similar to the initial meta-analysis (SMD 0.69 vs.

0.73). If we restricted trials to those using the HRSD (20 of 37 contrasts), the overall SMD was

similar to that using other scales (0.72 vs. 0.72 respectively).

We then performed planned sensitivity analyses to assess the effects of more restrictive

trial selection (Table 2). Restricting trials to those with a minimum age of 60 years or to those

with face-to-face psychotherapy had no significant effect on the SMD. Limiting the sample to

trials that only included MDD lowered the SMD from 0.73 to 0.64. The SMD was similar in

face-to-face therapy and bibliotherapy but somewhat larger in trials using group therapy than

those with individual therapy. The magnitude of these differences appeared substantially smaller

than the differences in SMD obtained with different types of control groups. One exception was

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therapy provided in the home, which appeared significantly more effective than therapy

administered in a clinic, although only 4 trials provided home care.

Exploratory analyses revealed that the SMD was modestly associated with trial duration;

strongly associated with study quality, sample size, and year of publication; and not significantly

associated with mean age, depression severity, or number of sessions (Table 2). Because some

factors were interrelated, we estimated and tested a regression model to assess their independent

contribution to the SMD, controlling for type of control group. While the overall model was

significant (p<.003) with R2=.56, no individual factor was significantly associated with the

SMD; however, we note that the power of this analysis to detect differences is limited by the

number of contrasts (N=37) (see Table, Supplemental Content 3, of the regression analysis). To

assess historical trends we examined the association of year of publication with the factors

detailed above weighting by sample size. Recent trials were of higher quality (r=0.68, df= 25;

p<.001), and mean age was greater (r=0.57, df=25; p=.002), but year of publication was not

associated with sample size, trial duration, depression severity, or number of sessions.

Publication bias

A funnel plot of the standard error of the SMD against the SMD indicated an excess of small

studies with large SMDs suggestive of bias (see Figure, Supplemental Digital Content 4, of the

funnel plot). The Egger test was significant (parameter estimate = 2.93, t = 3.77, df=1, p=.0006).

Sample size was inversely associated with the SMD, r = -0.46,, df = 35, p=.005). Exploratory

analysis of change in control groups

To explore differences in changes occurring within different types of control groups, we

calculated the within group standardized mean difference (SMD) for each of the control

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subgroups (Figure 3). Change in waitlist controls was quite small (SMD=0.11, 95% CI -0.04,

0.27). Change was greatest in the supportive therapy controls (SMD=1.10, 95% CI 0.81, 1.40).

Change in the TAU, attention, and placebo control subgroups was intermediate (SMD ranged

from 0.37 to 0.9)

Conclusions

Our meta-analysis confirmed previous findings that psychotherapy is an effective

treatment for depression in late life (4-7). As hypothesized, the magnitude of the effect varied

significantly by the type of control group. Furthermore, the effect of type of control on the SMD

was relatively large compared to other factors (Table 2). Psychotherapy interventions yielded

large effects when compared to waitlist and attention controls but small to moderate effects when

compared to supportive therapy. Contrary to our hypothesis, the effect size of psychotherapy

versus TAU was small to moderate.

Previous authors have emphasized the importance of controlling for non-specific effects

during treatment such as attention, reassurance, education and monitoring symptoms (8,10).

Supportive therapy best controls for these elements (8,10,18,43) and our findings indicate that

supportive therapy itself is associated with substantial improvement. Although the effect size for

psychotherapy was modest when compared with supportive therapy, the effect size was notable

when compared with the effect size of drug-placebo differences in late-life depression (ES =

0.14) (2). Comparisons with antidepressant trials are complicated by recent findings of negative

expectation effects in placebo-controlled studies (44,45). Specifically, patients receiving

antidepressants in trials with a placebo have significantly lower response rates compared to

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blinded trials without a placebo (52% vs. 65%) (45). Because patients cannot be blinded in

psychotherapy trials, rates of response may be higher than those usually encountered in placebo-

controlled drug trials. It remains unclear how expectation influences response in the control

condition in psychotherapy trials.

Five trials compared psychotherapy with supportive therapy. Four of these trials were

small pilot studies with N ≤ 25 subjects. Three of the five trials employed PST, including the

only large study in this group (N = 221). This was a high quality study (by RCT-PQRS rating)

for which the SMD was 0.33. Problem-solving therapy is the only psychotherapy in older adults

validated against a supportive therapy control (18). This finding underscores the paucity of

adequately powered psychotherapy trials with a supportive therapy control.

One purpose of the control condition is to account for spontaneous remission. Subjects

assigned to waitlist groups showed little change (SMD=0.11) suggesting low spontaneous

remission rates. This effect size is smaller than that reported by Rutherford et al. (46), who found

a within-group effect size of 0.5 for change in waitlist control subjects in 10 mixed-age trials. It

is possible the longer duration of treatment (10 vs. 7 weeks), greater depression severity (mean

HRSD 21 vs. 17), and younger mean age of patients in those trials resulted in greater change in

their waitlist controls than in ours.

Authors of a prior meta-analysis of psychotherapy trials in late-life depression found

significant heterogeneity in the included trials, which limited their conclusions (7). Our meta-

analysis addressed this limitation, in part, by examining treatment-control differences within

different types of control groups. The meta-analytic estimate of heterogeneity was <1% in

supportive therapy or placebo-controlled trials. Heterogeneity was greatest in the trials using

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attention (I2=93%), TAU (I2=71%), and waitlist control trials (I2 = 34%). It seems possible that

the variability of treatments in the TAU controls contributed to heterogeneity.

In addition among the trials with a TAU control, one trial (24) had a much larger SMD

and appeared to be an outlier. If that trial was removed, heterogeneity (I2) in the TAU controlled

trials was reduced from 71% to 0%. The Gellis et al trial (24) provided PST in the home, and it is

possible that home care in home-bound subjects may show greater differences when compared

with usual care. In fact, the SMD in the 4 home care trials was larger than the 26 contrasts in

which therapy was provided in a clinic (SMD 1.20 vs. 0.66).

The nature of the attention controls varied and may have contributed to the heterogeneity

in those trials. It is possible that subjects perceived some attention activities (e.g watching TV or

discussing current events) as less credible therapies. It is unclear what accounted for the

heterogeneity in the waitlist controls, although limiting trials to those with subjects aged ≥60

years reduced heterogeneity. Finally, the presence of heterogeneity does not negate our findings,

but rather suggests that other unidentified factors contributed to differences in efficacy between

therapy and control in the waitlist, TAU, and attention control groups.

The funnel plot and Egger’s test of the combined trials suggested potential bias; however,

the funnel plots differed among the trials with different controls. Trials with supportive therapy

and trials with placebo controls had symmetrical funnel plots each anchored by one large study.

The funnel plot of the trials with TAU controls was asymmetric but asymmetry was reduced with

exclusion of the Gellis trial (24). The funnel plots of the waitlist and attention controlled trials

were relatively uninformative, yet the mean SMDs for these trials were considerably higher than

those of the other control subgroups. Eighteen of the 21 contrasts using waitlist or attention

controls were from small trials (< 30 subjects per arm). When the contrasts using WL or AC

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were added to the combined group, they produced an apparent excess of small trials with large

SMDs. While we would be cautious about drawing conclusions given the small number of trials

in some subgroups, these data suggest the possibility that the asymmetry observed in the funnel

plot of the combined trials was the result of true differences in SMDs among the control

subgroups rather than publication bias.

In our meta-regression analyses, trial quality was inversely related to the SMD. Quality

and methodological rigor appeared to improve in recent studies resulting in more conservative

estimates of effects. Studies that were larger also tended to yield smaller effect sizes. Among

other factors examined, provision of therapy in the home stood out as having a relatively large

effect; however, this finding was based on just 4 trials.

Recent work by Rutherford and colleagues (47) suggests that other factors may influence

response in the control group, specifically in patients receiving placebo and clinical management.

They examined 11 placebo controlled antidepressant trials in older depressed adults. They found

that response rates in the control group increased with number of visits. The data in our

supportive therapy and placebo control samples were too limited to investigate this association.

We found no new comparison trials since Cuijpers’ 2006 review (5). Reminiscence

therapy was less effective than the other intervention in two trials (17,48). Most trials found no

significant difference between the psychotherapies, but caution is warranted before concluding

that these treatments were similarly efficacious. None of the comparison trials was adequately

powered to establish equivalence (see Text, Supplemental Digital Content 5, which describes the

comparison trials).

There are limitations to our study. First, we used an inclusive approach to trial selection;

however, our sensitivity analyses suggested this approach had little effect on the magnitude of

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the therapy-control difference. Second, we found significant heterogeneity in the overall sample

and in the waitlist, TAU, and attention control groups; however, some of the heterogeneity in the

overall analysis was explained by the different control groups employed. Third, year of study

was highly correlated with study quality, and both were inversely related to the SMDs.

Combining studies over a period of 30 years likely diluted the results of recent, higher quality

studies. Fourth, the analysis of other factors (e.g. age, severity) was limited to mean values for

the trial. Different results might be obtained with an individual patient-level analysis. Lastly, we

performed a number of exploratory analyses without correcting for multiple comparisons.

Our results indicate that psychotherapy is effective in older depressed adults and that the

magnitude of the effect varies considerably with the type of control. The large within-group

effect that occurs with supportive psychotherapy underscores the importance of controlling for

the non-specific effects of all supportive interventions. Compared with supportive therapy,

psychotherapy has a moderate effect size of about 0.3 to 0.4, which appears to be a reasonable

current estimate of the efficacy in older adults. Although smaller than reported in prior reviews,

this is a meaningful effect. Problem-solving therapy has the strongest evidence base using

supportive therapy as a control, but only one of these trials was large. The superiority of one

therapy over another in depressed elders using direct comparisons has not been established.

The results of our study emphasize the importance of selecting appropriate control groups

in future psychotherapy trials. Our findings indicate that the magnitude of psychotherapy effects

will vary with the type of control employed. Although a waitlist condition may control for time,

these data suggest the change associated spontaneous improvement is slight. Alternatively

change associated with supportive therapy or placebo plus clinical management is considerable.

If the intent of a psychotherapy trial is to demonstrate that a specific form of psychotherapy is

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superior to non-specific supportive effects of clinic visits, then a supportive therapy control is

required. If the intent is to determine effectiveness relative to current practice, then a treatment-

as-usual control is appropriate.

A TAU control might be especially appropriate if the intervention focuses on clinical

management. If a TAU control is employed, investigators should report what treatments were

actually received. A TAU control should not be employed when the research question is whether

a new therapy is as effective or superior to a common current treatment. In that case, the trial

should be designed as a comparison trial so that the “best practice” of each treatment is

compared. Given the effectiveness of supportive clinic visits, the role and value of the waitlist or

attention control conditions seem questionable. Finally, given the central role of non-specific

supportive elements in both psychotherapy and clinical management during antidepressant

treatment, investigation of the therapeutic effects of these elements is essential.

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Figure Legend

Figure 1. Search flow: trials identified and search process

Figure 2. Standardized mean differences for each treatment-control contrast, for each subgroup by type of control, and for all trials combined using a random effects meta-analysis Figure 3. Standardized Mean Difference and 95% confidence interval for change within each type of control group.

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Table 1. Characteristics of Included Trials

Authors Year Definition of Depression Minimum Age

Na Treatment Conditions Trial Duration

# Sessions

Alexopolous et al. (16) 2003 MDD + HRSD≥18 65 12 PST 12 12 13 ST 12 Arean et al. (17) 1993 MDD + HRSD≥18 + BDI≥20 + GDS≥10 55 19 PST-GP 12 12 20 REM-GP 12 20 WL NA Arean et al. (18) 2010 MDD + HRSD≥20 60 110 PST 12 12 111 ST 12 Beutler et al. (19) 1987 MDD + HRSD≥18 65 16 CT-GP + PC 20 NR 15 PC NR Ekkers et al. (20) 2011 MDD with rumination + GDS≥11 65 53 Competitive Memory Training + TAU 7 7 38 TAU NR Floyd et al. (21) 2004 MDD or MinorD or DD + HRSD≥10 60 13 Biblio 4 NA 8 CT 8 14 Delayed treatment (WL) NA Fry (22) 1983 BDI ≥ 19 65 54 Structured REM 5 5

54 Unstructured REM 5 54 AC 5 Gallagher (23) 1981 MMPI D-scale 2 SDs above mean 65 10 BT-GP 5 10 10 ST-GP 10 Gellis et al. (24) 2007 CES-D≥22 65 20 PST 8 6

20 TAU NR Hanser and Thompson 1994 MDD or Minor D 61 10 Home-based music CBT 8 8 (25) 10 WL NA Haringsma et al. (26) 2006 MDD 55 21 Coping with Depression-GP 10 10

22 WL Joling et al. (27) 2011 CES-D >16; Not MDD 75 86 CBT-Biblio 9 3

84 TAU NR Kiosses et al. (28) 2010 MDD + HRSD≥17 65 13 PATH 12 NR

12 ST 12 Laidlaw et al. (29) 2008 MDD + HRSD 7-24 + BDI 13-28 60 20 CBT 8 8c

20 TAU NR Lamers et al. (30) 2010 DD or minorD or mild-mod 60 127 MPI 6 4c MDD + HRSD≤18 135 TAU NR Landreville and 1997 GDS ≥11 55 10 CT-Biblio 4 NA Bissonnette (31) 13 Delayed treatment (WL) NA Mossey et al. (32) 1996 GDS≥11 + no current MDD or DD 60 31 IPC 12 10 38 TAU 10

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Rokke (33) 2000 MDD 60 9 Self-management therapy-GP 10 10 9 Education and support GP (ST) 10 16 Treatment on Demand (WL) NA Scogin et al. (34) 1987 HRSD≥10 60 9 CT Biblio 4 NA 8 AC Biblio NA 8 Delayed treatment (WL) NA Scogin et al. (35) 1989 HRSD≥10 60 21 CT Biblio 4 NA 19 BT Biblio NA 21 Delayed treatment (WL) NA Serfaty et al. (36) 2009 depression + BDI≥14 65 59 CBT + TAU 16 7c 56 Talking control (AC) + TAU 8c 52 TAU NR Serrano et al. (37) 2004 CES-D≥16 65 20 Life review therapy 6 6 23 No treatment (WL) NA Sloane et al. (38) 1985 MDD + HDRS≥17 60 19 IPT 6 6 10 Nortriptyline 6 14 PC 6 Thompson et al. (39) 1987 MDD + HRSD≥14 + BDI ≥17 60 27 CT 6 16-20 25 BT 16-20 24 Brief Psychodynamic Therapy 16-20 19 Delayed treatment (WL) NA van Schaik et al. (40) 2006 Depression + GDS≥5 55 69 IPT 22 8c 74 TAU NR Watt and Cappeliez (41) 2000 GDS≥14 60 12 Integrative REM-GP 6 6 9 Instrumental REM-GP 6 5 Socialization GP (AC) 6 Williams et al. (42) 2000 DD or minorD + HRSD≥10 60 138 PST + PC 11 6 140 PC 6

AC=attention control, BDI=Beck Depression Inventory, Biblio=bibliotherapy, BT=behavioral therapy, CBT=cognitive-behavioral therapy, CES-D=Center for Epidemiological Studies-Depression Scale, COPD=chronic obstructive pulmonary disease, CT=cognitive therapy, DD=dysthymic disorder, DM=type II diabetes mellitus, GDS=Geriatric Depression Scale, GP=group treatment, Home=Home-based care setting, HRSD=Hamilton Rating Scale for Depression, IPC=interpersonal counseling, IPT=interpersonal therapy, MDD=major depressive disorder MinorD=minor depression, MMPI D-scale=Minnesota Multiphasic Personality Inventory depression scale, MOS=months, MPI=minimal psychological treatment (elements of CBT, PST, and self-management), NR=not reported, OUT=Outpatient setting, PATH=home-delivered problem adaptation therapy, PC=placebo control, PST=problem-solving therapy, REM=reminiscence therapy, ST=supportive therapy, TAU=treatment as usual, usual care, WK=weeks, WL=waitlist control a. total number analyzed and reported (ITT if available or completer sample) b. Table shows contrasts were included in our analysis. c. Mean number of sessions

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Table 2. Potential Moderators of Treatment-Control Differences

a. Test for differences between the categories defined b. Excluding bibliotherapy c. Correlation of the variable with the SMD weighted for sample size

(revised Jan 2014)

Dichotomous Variables Number

Contrasts SMD 95% CI I2 Testa, df, p

All Studies 37 0.73 0.51, 0.95 84% Type of Control Waitlist 15 0.94 0.71, 1.17 34% X2=35.67, df=4,

p<0.00001 TAU 8 0.28 0.02, 0.53 71% Attention Control 6 1.36 0.36, 2.37 93% Supportive Therapy 5 0.39 0.16, 0.61 0% Placebo Control 3 0.05 -0.16,0.26 0% Type Depression Major Depression only 15 0.64 0.42, 0.87 49% X2=2.79, df=1

p=0.09 Other Depression 22 0.79 0.46, 1.12 89% Minimum Age ≥ 55 years 5 0.77 0.04, 1.50 86% X2=0.02, df=1,

p=0.89 ≥ 60 years 32 00.88 0.62, 1.14 87% Face-to-Face Therapy Yes 30 0.73 0.48, 0.98 86% X2=0.31, df=1,

p=0.58 No 7 0.73 0.21, 1.26 75% Type of Therapy Individual 21 0.72 0.42, 1.02 89% X2=6.45, df=2,

p=0.04 Group 8 0.81 0.36, 1.27 60% Bibliotherapy 7 0.73 0.21, 1.26 75% Site of Careb Home Care 4 1.20 0.72,1.68 33% X2=14.14, df=1, Clinic 26 0.66 0.40, 0.93 86% p=0.0002

Continuous Variables Number

Contrasts rc p

Mean Age 37 -0.28 0.09 Trial Duration 37 -0.40 0.01 Number Sessions 30 0.03 0.84 Depression Severity 37 0.31 0.06 Study Quality 37 -0.58 0.0002 Sample Size 37 -0.46 0.005 Year publication 37 0.65 <0.0001

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Supplemental Materials

1. Conversion of scales used to an equivalent 17-item HRSD score (.docx)

2. Description of trials excluded in this study but included in prior reviews (.docx)

3. Regression analysis of other factors on the standardized mean difference (SMD)

weighted for sample size and controlling for type of control group in 27 late-life

depression psychotherapy trials with 37 contrasts (.docx)

4. Funnel plot of psychotherapy trials (.tiff)

5. Comparison trials (.docx)

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1. Conversion of scales used to estimate 17-item HDRS scores

In order to estimate baseline depression severity for the meta-regression of associated

factors, we converted all scales to an equivalent 17-item HDRS score. To convert different

versions of the HRSD to the HRSD17 we used a proportion based on the maximum possible value

in non-psychotic patients. To convert Beck and GDS scores we calculated an average conversion

factor using all studies in this sample that reported both the HRSD and the Beck or the HRSD

and the GDS. No trial in this sample used the CES-D with the HDRS. We calculated an average

conversion factor from two other trials that used both the CES-D and the HDRS in 231 depressed

patients (1, 2).

1. Kim JY, Park JH, Lee JJ, et al. Standardization of the Korean version of the geriatric

depression scale: reliability, validity, and factor structure. Psychiatry Investig

2008;5:232-238.

2. Vieta E, deArce R, Jimenez-Arriero MA et al. Detection of subclinical depression in

bipolar disorder: a cross sectional, 4-month prospective follow-up study at community

mental health services (SIN-DEPRES). J Clin Psychiatry 2010;71:1465-1474.

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2. Description of trials excluded in this study but included in prior reviews

Thirteen articles cited in other reviews were not included. In two articles data was

insufficient and could not obtained (1,2) We also excluded three comparison trials with no

control group (3-5), duplicate reports of included trials (6-9), trials that did not assess stand-alone

psychotherapies (10-12), and a trial in which psychotherapy was one part of a collaborative care

program (13).

References

1. Campbell JM. Treating depression in well older adults: use of diaries in cognitive

therapy. J Consult Clin Psychol 1992;66:7-18.

2. Fry PS. Cognitive training and cognitive-behavioral variables in the treatment of

depression in the elderly. Clin Gerontol 1984;3:25-45.

3. Gallagher DE, Thompson LW. Treatment of major depressive disorder in older adult


4. Klausner EJ, Clarkin JF, Spielman L. Late-life depression and functional disability: the

role of goal-focused group psychotherapy. Int J Geriat Psychiatry 1998;13:707-716.

5. Thompson LW, Coon DW, Gallagher-Thompson D. Comparison of desipramine and

cognitive/behavioural therapy in the treatment of elderly outpatients with mild-to-

moderate depression. Am J Geriatr Psychiatry 2001;9:225-240.

6. Barrett JE, Williams JW, Oxman TE, et al. The Treatment Effectiveness Project. A

comparison of the effectiveness of paroxetine, problem-solving therapy, and placebo in

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the treatment of minor depression and dysthymia in primary care patients: background

and research plan. General Hospital Psychiatry 1999;21:260–273.

7. Breckenridge JS, Zeiss AM, Breckenridge JN, et al. Solicitation of elderly depressives for

treatment outcome research: a comparison of referral sources. J Consult Clin Psychol

1985;53(4):552–4

8. Floyd M. Cognitive therapy for depression: a comparison of individual psychotherapy

and bibliotherapy for depressed older adults. Tuscaloosa: University of Alabama;

dissertation, 1998

9. Thompson LW, Gallagher D. Efficacy of psychotherapy in the treatment of late-life

depression. Adv Behav Res Ther 1984;6:127-139

10. Latour D, Cappeliez P. Pretherapy training for group cognitive therapy with depressed

older adults with a disability. Can J Aging 1994;13:221-235.

11. Lynch TR, Morse JQ, Mendelson T, et al. Dialectical behavior therapy for depressed

older adults: a randomized pilot study. Am J Geriatr Psychiatry 2003; 11:33-45.

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depression treatment in older adults; A randomized controlled trial. JAMA

2004;291:1569-1577.

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3. Regression analysis of other factors on the standardized mean difference (SMD) weighted for

sample size and controlling for type of control group in 27 late-life depression psychotherapy

rrials with 37 contrasts

Parameter Estimate

df t-test p

Mean Age 0.024 1 0.87 0.39 Trial Duration 0.009 1 0.36 0.72 HDRS17 total 0.025 1 1.05 0.30 Study Quality -0.039 1 -1.40 0.17 Sample Size 0.001 1 0.83 0.41 Year of pub -0.029 1 -1.50 0.15

Although the overall model was significant (p < .003) with the adjusted r2 = .56, no individual

factor was significantly associated with the SMD; however, we note that the power of this

analysis to detect differences is limited by the number of contrasts (N=37).

Revised Feb 26, 2014

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5. Comparison trials

Our search identified 9 trials that compared active psychotherapies. Six of those trials (1-

6) were included in the preceding review of controlled trials. Three other comparison trials with

no control group were found (7-9). Our search did not identify any comparison trials published

since the Cuijpers review (10). Different from that review we did not include Gallagher 1981

(11) because we considered supportive therapy a type of control group. We did not include

Latour 1994 (12) because this was not a stand-alone treatment, and we did not include the

Thompson article from 1984 (13) which was an interim report published in final form in 1987

(5).

These 9 trials included 13 contrasts of which 10 were unique contrasts of different pairs,

e.g. PST vs. reminiscence, CT vs BT, CBT vs. dynamic, etc. The trials included 381 patients.

The largest had 54 in each arm, one other had an average of 25 per arm, and the other 7 trials had

less than 25 subjects per arm. Four of the trials were 4-6 weeks in length, four were 11-16 weeks,

and one was 36 weeks. Five of the trials were limited to subjects with MDD, the others included

other DSM depression diagnosis or defined depression with a scale threshold score. Only one of

the trials reported data from an intention-to-treat analysis, the others reported outcome in

completers.

Of the 13 contrasts of two psychotherapies, only 3 differed significantly. PST was more

effective than reminiscence therapy (1), structured reminiscence therapy was more effective than

unstructured reminiscence (3), and found goal-focused group therapy more effective than

reminiscence therapy (8). Because 10 contrasts were unique and 3 contrasts were only examined

twice, a meta-analysis did not appear indicated (i.e. there was no standard treatment with which

others could be compared).

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Ten of the contrasts found no significant difference between therapies; however, we

would be cautious about concluding that they have similar efficacy. As noted above, only one of

the contrasts included more than 30 subjects per arm, the minimal number recommended for

treatment trials in depression (14). None of the comparisons were of sufficient size to establish

equivalence.

References

1. Arean PA, Perri MG, Nezu AM, Schein RL, Christopher F, Joseph TX. Comparative

effectiveness of social problem-solving therapy and reminiscence therapy as treatments

for depression in older adults. J Consult Clin Psychol 1993;61:1003-10.

2. Floyd M, Scogin F, McKendree-Smith NL, Floyd DL, Rokke PD. Cognitive therapy for

depression: a comparison of individual psychotherapy and bibliotherapy for depressed

older adults. Behav Modif 2004;28:297-318.

3. Fry PS. Structured and unstructured reminiscence training and depression among the

elderly. Clin Gerontol 1983;1:15-37.

4. Scogin F, Jamison C, Gochneaur K. Comparative efficacy of cognitive and behavioral

bibliotherapy for mildly and moderately depressed older adults. J Consult Clin Psychol

1989;57:403-7

5. Thompson LW, Gallagher D, Breckenridge JS. Comparative effectiveness of

psychotherapies for depressed elders. J Consult Clin Psychol 1987;55:385-90

6. Watt LM, Cappeliez P. Integrative and instrumental reminiscence therapies for

depression in older adults: intervention strategies and treatment effectiveness. Aging

Ment Health. 2000;4:166-77.

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7. Gallagher DE, Thompson LW. Treatment of major depressive disorder in older adult


8. Klausner EJ, Clarkin JF, Spielman L. Late-life depression and functional disability: the

role of goal-focused group psychotherapy. Int J Geriat Psychiatry 1998;13:707-716.

9. Steuer JL, Mintz J, Hammen CL, Hill MA, Jarvik LF, McCarley T, Motoike P, Rosen R.

Cognitive-Behavioral and Psychodynamic Group Psychotherapy in Treatment of

Geriatric Depression. J Consult Clin Psych 1984;52(2):180-189

10. Cuijpers P, van Straten A, Smit F. Psychological treatment of late-life depression: a meta-

analysis of randomized controlled trials. Int J Geriatr Psychiatry 2006; 21(12):1139-49.

11. Gallagher D. Behavioral group therapy with elderly depressives: An experimental study.

Upper D. & Ross S. (Eds). Behavioral group therapy. Champaign: Research Press 1981;

187-224.

12. Latour D, Cappeliez P. Pretherapy training for group cognitive therapy with depressed

older adults with a disability. Can J Aging 1994; 13:221-235.

13. Thompson LW, Gallagher D. Efficacy of psychotherapy in the treatment of late-life

depression. Adv Behav Res Ther 1984; 6:127-139

14. Lieberman JA, Greenhouse J, Hamer RM, Krishnan KR, Nemeroff CB, Sheehan DV,

Thase ME, Keller MB. Comparing the effects of antidepressants: consensus guidelines

for evaluating quantitative reviews of antidepressant efficacy. Neuropsychopharmacology

2005;30(3):445-60.

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