Interventions for generalized anxiety disorder in older adults: Systematic review and meta-analysis

Journal of Anxiety Disorders 26 (2012) 1–11

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Journal of Anxiety Disorders

Review

Interventions for generalized anxiety disorder in older adults: Systematic review and meta-analysis Daniela C. Gonc¸alves a,∗ , Gerard J. Byrne a,b a b

School of Medicine, University of Queensland, Brisbane, Australia Royal Brisbane & Women’s Hospital, Brisbane, Australia

a r t i c l e

i n f o

Article history: Received 5 May 2011 Received in revised form 12 August 2011 Accepted 12 August 2011 Keywords: Generalized anxiety disorder Intervention Older adults Treatment

a b s t r a c t Introduction: Generalized anxiety disorder (GAD) is one of the most common anxiety disorders in later life, with widespread consequences for individuals and society. Objective: To perform a systematic review of the efficacy of controlled interventions for GAD in adults aged 55 years and older. Method: Direct search of digital databases and the main publications on aging and iterative searches of the references from retrieved articles. Results: Twenty-seven trials (14 pharmacological, 13 psychotherapeutic) fulfilled the inclusion criteria, reporting results from 2373 baseline participants. There were no differences between trials in their overall quality. Pooled treatment effects for pharmacological (OR = 0.32, 95% CI: 0.18, 0.54) and psychotherapeutic (OR = 0.33, 95% CI: 0.17, 0.66) trials were similar, with findings in each case favoring active interventions over control conditions. Conclusions: Older adults with GAD benefited from both pharmacological and psychotherapeutic interventions. Future studies should investigate combined treatment with medication and psychotherapy. © 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2.

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4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Data abstraction and validity assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Qualitative analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Quantitative data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Recent research on late-life anxiety disorders has failed to confirm some previously held beliefs, including the notions that

∗ Corresponding author at: Academic Discipline of Psychiatry, School of Medicine, University of Queensland, K Floor, Mental Health Centre, Royal Brisbane & Women’s Hospital, Queensland 4029, Australia. Tel.: +61 7 3365 5572; fax: +61 7 3365 5488. E-mail address: [email protected] (D.C. Gonc¸alves). 0887-6185/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.janxdis.2011.08.010

1 2 2 2 3 3 3 4 4 7 10 10 10

anxiety disorders rarely have their onset in later life or usually occur in comorbid relation to other disorders (Wetherell, Maser, & van Balkom, 2005). A recent review indicated that the prevalence of anxiety disorders ranged from 1.2 to 15% in community dwelling adults aged 55 years and older, and was almost twice as high in clinical settings (Bryant, Jackson, & Ames, 2008). In a national representative sample of community dwelling adults the prevalence of anxiety disorders was twice as high as the prevalence of mood disorders (Byers, Yaffe, Covinsky, Friedman, & Bruce, 2010). Generalized anxiety disorder (GAD) is one of the most common anxiety

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disorders in older adults, with surveys conducted with representative older cohorts obtaining 12-month rates between 1.0 (Grant et al., 2005) and 7.3% (Beekman et al., 1998). Anxiety symptoms and disorders have widespread consequences for the person and the society. At an individual level, anxiety symptoms and disorders have been found to be associated with increased sleep disturbance (Brenes et al., 2009), intake of anxiety related medication (Gonc¸alves, Pachana, & Byrne, 2011), disability (Brenes et al., 2005), mortality (Ostir & Goodwin, 2006), and decreased cognitive functioning (Beaudreau & O’Hara, 2009; Mantella et al., 2007). At a societal level, late-life anxiety was related to increased use of health services, namely longer appointments with physicians (Stanley, Roberts, Bourland, & Novy, 2001), and inability to perform daily functions (Trollor, Anderson, Sachdev, Brodaty, & Andrews, 2007). GAD has a low likelihood of spontaneous remission (Lenze, Mulsant, Mohlman, et al., 2005). An observational longitudinal study of community dwelling older adults found that at a 3year follow-up more than half of those diagnosed with GAD at baseline fulfilled criteria for a mental health disorder (Schoevers, Deeg, van Tilburg, & Beekman, 2005). Despite the high prevalence, widespread impact and chronic course of the disorder, individuals with this disorder seldom seek the help of mental health professionals (Hunt, Issakidis, & Andrews, 2002), and there is a two-year mean delay between the onset of the disorder and the initiation of treatment (Grant et al., 2005). Older adults are even less likely than young and middle aged people to seek help from a mental health professional, with the primary care physician being the first choice of the majority of older people with anxiety disorders (De Beurs et al., 1999). However, contrary to what has been previously believed, older adults seem to display positive attitudes towards mental health professionals and would be willing to accept help if offered (Arean, Alvidrez, Barrera, Robinson, & Hicks, 2002; Mackenzie, Scott, Mather, & Sareen, 2008). A recent survey conducted with a sample of healthy older adults showed that when confronted with a hypothetical scenario of an anxiety disorder, three quarters of the participants chose psychotherapy as the preferred treatment, with the remaining participants selecting either pharmacotherapy or combined treatment (Mohlman, in press). In comparison with other anxiety disorders, GAD has been neglected by researchers, with a relative paucity of published research devoted to this disorder (Byrne & Pachana, 2010; Dugas, Anderson, Deschenes, & Donegan, 2010). There is an even more limited literature on the treatment of late-life GAD, in comparison with reports of treatment trials in other age groups and for other disorders. As older adults have an increased likelihood of comorbid physical disorders and polypharmacy, pharmacological trials have often used older age as an exclusion criterion (e.g., Enkelmann, 1991; Lecrubier, Puech, Azcona, Bailey, & Lataste, 1993). Even in those trials in which no age ceiling was defined, the proportion of older adults has been relatively small, with studies reporting an average sample age of approximately 40 years (e.g., Gelenberg et al., 2000; Rickels, Schweizer, DeMartinis, Mandos, & Mercer, 1997). The limited recognition given to anxiety disorders in later life, along with the reluctance of older people to seek consultations with mental health professionals, might partially explain the sparseness of psychotherapeutic trials (Wetherell, Lenze, & Stanley, 2005). However, over the past decade there has been a gradual change in this trend, with an increasing number of treatment trials on anxiety disorders in older people being reported. Recent studies have reported on the efficacy of both pharmacological and psychotherapeutic interventions, with published reports generally favoring treatment over a control condition (Nordhus & Pallesen, 2003). Effect sizes for both clinician-rated and self-rated anxiety were found to be moderate to large for behavioral interventions and

large for pharmacological interventions (Pinquart & Duberstein, 2007). In older people with a variety of different anxiety disorders, cognitive behavioral therapy (CBT) has been found to be significantly more effective in worry reduction than a waiting list control condition, although not more so than an active comparator (Hendriks, Voshaar, Keijsers, Hoogduin, & van Balkom, 2008). Conversely, another meta-analysis that included both controlled and uncontrolled trials found no additional gains to older adults with a variety of anxiety disorders when other CBT components were added to relaxation training alone (Thorp et al., 2009). Notwithstanding the previously published results, it should be noted that the comparison of treatment trials has been constrained by the range of different anxiety disorders studied and the diversity of control conditions employed. Against this background, we undertook a systematic review and meta-analysis of controlled interventions for GAD in older adults, namely pharmacological, psychological, behavioral and alternative or life-style therapies. The main goal was to identify studies that had been conducted with the purpose of treating GAD in older adults. Only studies that reported a control condition, either active or passive, were included. Studies were assessed using qualitative and quantitative parameters. The quality of studies was assessed through the quality rating system developed by the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDAN, Moncrieff, Chruchill, Drummond, & Mcguire, 2001). Quantitative analyses were conducted through random-effects analysis (DerSimonian & Laird, 1986), whereas publication bias was assessed using the funnel plot technique (Begg & Mazumdar, 1994). Because participant attrition can inflate results and reduce generalizability, we adopted an intent-to-treat approach to the analysis. This means that all baseline participants were included in the analysis, with drop-outs being rated as non-responders (Hollis & Campbell, 1999). 2. Methods 2.1. Search protocol During January 2011 four electronic databases (ISI Web of Knowledge; PsycINFO; PubMed; Cochrane) were searched for the terms older (adult* or person or people) or elder* or late-life or geriat*, combined with intervention or treatment or therapy or trial or randomized, and generalized anxiety disorder. No language or date restrictions were used. The Database of Abstracts of Reviews of Effects (DARE) and Dissertation Abstracts International (DAI) were also searched for the terms “generalized anxiety” along with older or elder*. A direct search on relevant aging publications (e.g., Journal of the American Geriatrics Society) was also performed, using the term “generalized anxiety”. The same direct search procedure was applied to a set of anxiety related journals (e.g., Journal of Anxiety Disorders), using the keywords “generalized anxiety” and “older”. Finally, systematic reviews and meta-analyses published over the past 10 years on this topic, as well as the papers retrieved and assessed as relevant, were screened for additional relevant references. Backward searching was conducted by investigating studies in the identified research papers and reviews, whereas forward searching was performed using the ISI Web of Knowledge citation identification system. 2.2. Inclusion criteria i. Participants aged ≥55 years or studies with a mean or median age of ≥60 years; ii. Study reported an established intervention (pharmacological, psychological, life style), with sufficient detail to be replicated;

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

iii. There was a clearly described parallel group design; iv. GAD was the primary diagnosis, established by diagnostic criteria (DSM or ICD) or expert clinical judgment (comorbidity was allowed as long as GAD was the main diagnosis); when results were presented together for several anxiety disorders, GAD had to be the main diagnosis of at least three fourths of the participants; v. Outcome was defined as response to the intervention, which was previously defined by the authors; the study provided enough detail to perform a meta-analysis of the data.

Initially retrieved abstracts: 1001 Duplicated results (same abstract found twice): 331 Initially retrieved original abstracts: 670 Disorders other than GAD (178), not intervention (120), reviews (108), younger samples (58), psychometric studies (52), other, e.g., editorial (56): 572

2.3. Data abstraction and validity assessment Studies were initially extracted for abstract screening and those found to be relevant were fully retrieved for a detailed review. Disagreements on eligibility were resolved by discussion between the authors. Once the studies to be included were established, data were extracted by both authors, specifically coding authorship, publication date, setting and country, study type (pharmacological or psychotherapy), intervention and control characteristics (dosage/number of sessions; length; active or passive control), recruitment method, exclusion and exclusion criteria, diagnostic system, diagnosis made, main outcome measures, secondary outcome measures, response definition, clinical and control group characteristics (number at baseline; dropout rate; mean age and percentage female), outcomes (proportion of response, average improvement on outcome measures) and existence of follow-up. Whenever necessary and if a contact was found, authors were contacted and asked to provide raw data. The quality of studies was assessed through the quality rating system developed by the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDAN), which is composed of 23 items that assess issues relevant for treatment trials, such as sample size and representativeness, method of allocation and outcome measures (Moncrieff et al., 2001). Scores on the CCDAN rating system range from 0 to 46, with higher scores indicating better quality. Along with quality assessment, clinical heterogeneity between studies was also considered through a qualitative judgment (Fletcher, 2007), specifically taking into account participant characteristics and the length of the intervention. The quantitative data synthesis consisted of four stepwise tasks: selecting which data should be included in the overall analysis, assessing statistical heterogeneity, estimating a common effect, and analyzing publication bias (Lau et al., 1997). Statistical heterogeneity was considered through the Q and the I2 statistics, as these are considered to provide complementary information regarding homogeneity (Huedo-Medina, Sanchez-Meca, Marin-Martinez, & Botella, 2006). Treatment effects were defined according to the number of participants who responded to the intervention, as defined by the authors of each trial, by the end of the pre-defined intervention period. Mid-treatment and follow-up measures were not considered. In this way, the effect measure was considered to be the odds ratio, established by the ratio between the two odds, that is, the odds of achieving response in the clinical group over the odds of achieving response in the control condition (Sterne, Bradburn, & Egger, 2001). An intention-to-treat approach was adopted, in the sense that all participants included in each arm at baseline were included in the proportion calculation (Hollis & Campbell, 1999). A random-effects analysis was employed (DerSimonian & Laird, 1986), as it was thought that the heterogeneity of studies (e.g., significantly different sample sizes) might violate any assumption of similar treatments. Publication bias was assessed using the funnel plot technique (Begg & Mazumdar, 1994). All analyses were performed using Stata 11 (StataCorp, 2009). This report follows the guidelines provided by the Quality of Reporting of Meta-analyses (QUORUM) group (Moher et al., 1999).

3

Papers retrieved for detailed screening: 98 Not controlled (15), anxiety symptoms in healthy sample (13), anxiety symptoms in other disorders (12), impact of psychotropics in older adults (7), no formal diagnosis (7), others, e.g., results presented together for several anxiety disorders where the majority did not have GAD (14): 68

Papers initially considered for the review: 30 Duplicated results (same results published twice): 5 Papers considered for the review: 25 (27 trials) Insufficient data to perform a meta-analysis: 7 trials Trials considered for the meta-analysis: 20 Fig. 1. Diagram of retrieved, excluded and included studies.

3. Results 3.1. Search results The search strategy identified 670 original titles (Fig. 1). Abstract screening resulted in the exclusion of 572 papers, with the main reasons for exclusion being a focus on a disorder other than GAD (178 papers) and reporting factors related with GAD, such as prevalence and risk factors, but not an intervention trial (120 papers). Of the 98 papers retrieved for detailed inspection, 67 were excluded as they failed to fulfill one or more inclusion criteria, such as having a control group (15 papers) and reporting formal diagnostic criteria (7 papers). Other common reasons for exclusion of papers at this stage included because they reported interventions to reduce anxiety symptoms in healthy older adults (13 papers) or in older adults with another disorder (12 papers). Thirty papers were thus

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considered to fulfill the inclusion criteria previously established. Of these, 5 were excluded as they were duplicate reports, leaving 25 papers that reported 27 trials to be included. Initial agreement was met for all except six studies. After discussion between the authors consensus was achieved, leading to the inclusion of three out of the six studies. 3.2. Qualitative analysis There was considerable clinical heterogeneity among studies. Table 1 presents detailed descriptive data for each trial. Two studies (Davidson et al., 2008; Katz, Reynolds, Alexopoulos, & Hackett, 2002) reported analysis of pooled data for older adults derived from previously published pharmacological trials of adult population. Taken together, the trials reported findings from 2373 baseline participants. Baseline sample sizes ranged from 8 (Mohlman, 2008) up to 450 (Eriksson, Mezhebovsky, Magi, She, & Datto, 2008). The mean number of participants for pharmacological interventions (n = 132) was significantly higher (t = 2.66, d.f. = 25, p = .01) than the mean number for psychotherapy (n = 40). Most trials reported an average age between 65 and 75 years. One of the trials was designed as an intervention for post-stroke comorbid GAD and MDD and reported an average age of 55 years for the control group (Kimura, Tateno, & Robinson, 2003), whereas another one reported an average age for the entire sample of 82.6 years (Majercsik & Haller, 2004). One trial included participants aged 60 years and older, but did not state their mean age (Di Costanzo & Rovea, 1992). Recruitment of participants was mainly achieved through professional referral and advertisement, except for one trial that also recruited nursing home residents (Cohn, 1984), another one that recruited outpatients from a psychiatric service (Di Costanzo & Rovea, 1992), and still another which invited inpatients from a geriatric hospital service to participate (Majercsik & Haller, 2004). Twenty-one trials included only participants that had GAD as the principal or co-principal diagnosis. Other diagnoses included were adjustment disorder with anxiety symptoms (Frattola et al., 1992; Koepke, Gold, Linden, Lion, & Rickels, 1982), anxiety disorder not otherwise specified (Gorenstein et al., 2005; Wetherell et al., 2009) and panic disorder (Gorenstein et al., 2005; Lenze, Mulsant, Shear, et al., 2005). The proportion of participants with GAD ranged from approximately three fourths up to the entire sample. Fourteen trials reported pharmacological interventions, using drugs from five broad classes. Five trials used antidepressants, including a tricyclic, two selective serotonin reuptake inhibitors (SSRI) and two serotonin and noradrenaline reuptake inhibitors. Four trials used sedative/hypnotic drugs, of which three were benzodiazepines. Two trials used an anticonvulsant, two trials used the piperazine/azapirone anxiolytic, buspirone, and one trial used the second-generation antipsychotic, quetiapine. Thirteen trials reported psychotherapeutic interventions, with cognitive behavioral therapy being used in at least one of the arms in twelve trials. Nine were conducted through individual sessions and four as group interventions. Psychotherapy trials had an average duration of 12 weeks (range 8–15 weeks), which was significantly higher than the 7-week average (range 3–12 weeks) reported for pharmacological interventions (t = −5.90, d.f. = 25, p < .001). One pooled pharmacological study (Katz et al., 2002) reported 24-month data for part of the sample, but only the week eight results were considered here, as this was the common intervention period between the trials pooled by the authors. Placebo was used as the control condition in all pharmacological trials except one, which compared the efficacy of buspirone with sertraline (Mokhber et al., 2010). In the psychotherapeutic trials, the most common control conditions were waiting list (four trials), followed by usual care or enhanced usual care (four trials). The main

difference between these two groups of control conditions was that in the later condition participants were contacted by phone more frequently (e.g., Stanley, Beck, et al., 2003), than in trials that used a waiting list (e.g., Mohlman et al., 2003) and each participant’s general practitioner was informed of the mental health diagnosis made by the researchers (Stanley et al., 2009; Wetherell et al., 2009). In addition, two psychotherapeutic trials used an active control condition (Gorenstein et al., 2005; Wetherell, Gatz, & Craske, 2003), and three trials compared two different psychotherapy protocols, with CBT being always used in one of the arms (Mohlman, 2008; Stanley, Beck, & Glassco, 1996; Wetherell, Liu, et al., 2011). None of the pharmacological trials reported a 6-month or greater follow-up period, whereas 10 of the 12 psychotherapy trials did. Response definition was highly heterogeneous. Some pharmacological trials defined response as decrease of baseline anxiety scores of at least 25% (e.g., Bresolin et al., 1988; Frattola et al., 1992), whereas others required a decrease of at least 50% (e.g., Kimura et al., 2003). Some studies defined a response as having received a clinician rating of being improved or much improved (e.g., Lenze et al., 2009) or required a combination of a clinician rating and a change from baseline in a score (Montgomery, Chatamra, Pauer, Whalen, & Baldinetti, 2008). Still other investigators considered that response was achieved when GAD was no longer diagnosable and there was a decrease of at least one fifth in the majority of the outcome measures (e.g., Mohlman & Gorman, 2005; Stanley, Hopko, et al., 2003). Finally, some investigators did not report a response definition (Cohn, 1984; Majercsik & Haller, 2004). Another source of heterogeneity was participant attrition (dropouts). This ranged from zero participants to up to one third of the randomized sample. Dropout rates did not vary by type of intervention (t = −1.15, d.f. = 25, p = .26), although reasons for withdrawal were diverse. We rated the overall quality of the trials as 27 (SD = 5.5, range 16–39), with an inter-rater agreement for the overall score of r = 0.75. Although intervention type was not related to trial quality (t = −0.25, d.f. = 25, p = .80), there was however a direct significant relation between the overall quality score and the publication year (r = 0.25, p = .01). 3.3. Quantitative data synthesis Four pharmacological (Cohn, 1984; Di Costanzo & Rovea, 1992; Koepke et al., 1982; Majercsik & Haller, 2004) and two psychotherapy (Wetherell et al., 2009; Wetherell, Liu, et al., 2011) interventions did not provide a definition of response in the published report, instead just analyzing the degree of change from baseline to post-treatment, and as such were excluded from the quantitative data synthesis. An additional pharmacological study (Mokhber et al., 2010) defined response but did not report summary response data and was also excluded. Meta-analyses were conducted separately for pharmacological and psychotherapeutic trials and displayed in forest plots (Figs. 2 and 3). Within pharmacological trials, results were analyzed according to broad drug classes (2 trials that used benzodiazepine or a benzodiazepine-like drug, 5 antidepressant trials, 2 trials that used other drugs). For psychotherapeutic trials treatment effects were considered according to the type of comparison condition (7 passive control/minimal contact trials, 2 active control trials, 2 trials with psychotherapy in both arms). Within pharmacological trials, treatment effects were highly heterogeneous (Q = 31.8, d.f. = 8, p < .0001; I2 = 75%, p < .001), perhaps reflecting the diversity of pharmacological agents used. The pooled odds ratio for the pharmacological trials was 0.32 (95% CI: 0.18, 0.54, z = 4.20, p < .001), favoring treatment with an active substance when compared with a placebo condition. When drug classes were considered separately, both benzodiazepines (OR = 0.19, 95% CI: 0.08, 0.47, z = 3.65, p < .001) and antidepressants

Table 1 Study characteristics of the trials considered for the review. Setting & country

Clinical group

Control group

Intervention & comparison condition

Length

Follow up

Comorbid depression excluded

Response definition

Drop-outs

Ratio of response (initial n considered)

CCDAN total score

Bresolin et al. (1988)

Community, multicentre, Italy

4 weeks

No

Yes

↓ 25% on OM

6% clinical 3% control

24/31 clinical 13/32 control

24

Outpatients & nursing home residents, USA Community, multicentre, USA

n = 32 76 years 69% ♀ n = 43 69 years 79% ♀ n = 28 71 years 46% ♀ n = 18 Ø Ø n = 227 70 years* Ø n = 20 71 years 75% ♀ n = 19 69 years 53% ♀ n = 48 65 52% ♀ n = 14 55 years 50% ♀ n = 112 68 years 66% ♀* n = 17 68 years 35% ♀ n = 92 72 years 63% ♀ n = 45 83 years 70% ♀* 13 66 years 54% ♀ n=7 67 years 50% ♀ n = 10 69 years 57% ♀*

Ketazolam vs. placebo

Cohn (1984)

n = 31 72 years 68% ♀ n = 40 69 years 68% ♀ n = 45 70 years 60% ♀ n = 18 Ø Ø n = 223 70 years* Ø n = 20 70 years 75% ♀ n = 23 68 years 48% ♀ n = 136 67 years 65% ♀ n = 13 65 years 54% ♀ n = 108 68 years 66% ♀* n = 17 71 years 88% ♀ n = 85 71 years 72% ♀ n = 105 83 years 70% ♀* 14 67 years 86% ♀ n=8 69 years 63% ♀ n = 22 69 years 53% ♀*

Alprazolam vs. placebo

4 weeks

No

No

Ø

5% clinical 30% control

N/A

22

Duloxetine vs. placebo

9/10 weeks

No

Yes

↓ 50% on OM or I/MI

33% clinical 29% control

20/45 clinical 8/28 control

29

Carbamazepine vs. placebo

4 weeks

No

Ø

Ø

0% clinical 0% control

N/A

17

Quetiapine XR vs. placebo

9 weeks

No

Ø

↓ 50% on OM

Ø

153/223 54/227 control

16

Alpidem vs. placebo

3 weeks

No

Yes

↓ 25% on OM

5% clinical 10% control

10/20 clinical 3/20 control

31

CBT+MM vs. MM

13 individual sessions 8 weeks

6 months

Yes

I/MI

39% clinical 26% control

9/23 clinical 5/19 control

32

No

Yes

↓ 50% on OM or I/MI

25% clinical 33% control

72/136 clinical 18/48 control

32

Nortriptypline vs. placebo

6–9 weeks

No

No**

↓ 50% on OM

8% clinical 0% control

9/13 clinical 3/14 control

23

Oxazepam vs. placebo

4 weeks

No

No

Ø

16% clinical 19% control

N/A

22

Citalopram vs. placebo

8 weeks

No

Yes

↓ 50% on OM or I/MI

18% clinical 12% control

11/17 clinical 4/17 control

31

Escitalopram vs. placebo

12 weeks

No

No

I/MI

19% clinical 18% control

49/85 clinical 42/92 control

39

Buspirone vs. placebo

6 weeks

No

Ø

Not defined

0% clinical 0% control

N/A

22

CBT vs. WL

13 individual sessions 13 individual sessions 13 individual sessions

6 months

Yesc

21% clinical 23% control

4/14 clinical 1/13 control

26

6 months

Yesc

0% clinical 0% control

6/8 clinical 1/7 control

26

Approx. 18 months

No

No GAD and ↓ 20% on 3/4 of OM No GAD and ↓ 20% on 3/4 of OM No GAD and ↓ 20% on 3/4 of OM

9% clinical 0% control

7/22 clinical 0/10 control

27

Davidson et al. (2008)

Di Costanzo and Rovea (1992)

Rehab centre outpatients, Italy

Eriksson et al. (2008)a

Ø

Frattola et al. (1992)

Community, two centre, Italy

Gorenstein et al. (2005)

Community, USA

Katz et al. (2002)

Community, multicentre, USA

Kimura et al. (2003)

Community, multicentre, USA

Koepke et al. (1982)

Community, multicentre, USA

Lenze et al. (2005a)

Community, USA

Lenze et al. (2009)

Community, USA

Majercsik and Haller (2004) Mohlman et al. (2003)b

Hospital inpatients, Hungary Community, USA

Mohlman et al. (2003)b

Community, USA

Mohlman and Gorman (2005)

Community, USA

Venlaxafine ER vs. placebo

Enhanced CBT vs. WL CBT vs. WL

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

Authors (year)

5

6

Table 1 (Continued) Setting & country

Clinical group

Control group

Intervention & comparison condition

Length

Follow up

Comorbid depression excluded

Response definition

Drop-outs

Ratio of response (initial n considered)

CCDAN total score

Mohlman (2008)

Community, USA

8 individual sessions 8 weeks

6 months

Yes

4/4 CBT+APT 2/4 CBT

26

No

Yes

No GAD and ↓ 20% on 3/4 of OM ↓ 50% on OM

0%CBT+APT 0% CBT

Psychiatric outpatients, Iran

n=4 67 years 50% ♀ n = 25 66 years 64% ♀

CBT+APT vs. CBT

Mokhber et al. (2010)

n=4 64 years 75% ♀ n = 21 67 years 48% ♀

Ø

20

Montgomery et al. (2008)

No

Yes

↓ 50% on OM and I/MI

85/177 clinical 35/96 control

37

SP vs. CBT

14 group sessions

6 months

Yes

↓ 20% in 3/4 of OM

31% CBT 35% SP

5/26 CBT 7/20 SP

26

Community, USA

CBT vs. MCC

15 group sessions

6 & 12 months

No

13/39 clinical 3/41 control

28

Community, USA

CBT/PC vs. UC

No

No

17% clinical 33% control

5/6 clinical 1/6 control

24

Stanley et al. (2009)

Community, USA

6, 9, 12 & 15 months

No

Meaningful changes OM

7% clinical 22% control

38/70 clinical 31/64 control

36

Wetherell et al. (2003)d

Community, USA

8 individual sessions Up to 10 individual sessions 12 group sessions

↓ 20% in symptom severity ↓ 20% in 2/3 of OM

26% clinical 10% control

Stanley et al. (2003b)

6 months

No

↓ 20% in 3/4 of OM

31% clinical 9% control

6/26 clinical 1/23 control

27

Wetherell et al. (2003)d

Community, USA

Wetherell et al. (2009)

Community, USA

Wetherell et al. (2011a)

Community, USA

n = 96 72 years 75% ♀ n = 26 68 71% ♀* n = 41 66 years 75% ♀* n=6 71 years 83% ♀* n = 64 67 years 77% ♀ n = 23 67 years 80% ♀* n = 26 67 years 80% ♀* n = 16 73 years 81% ♀ n=9 71 years 48% ♀*

8 weeks

Stanley et al. (2003a)

n = 177 72 years 79% ♀ n = 20 68 71% ♀* n = 39 66 years 75% ♀* n=6 71 years 83% ♀* n = 70 67 years 80% ♀ n = 26 67 years 80% ♀* n = 26 67 years 80% ♀* n = 15 71 years 87% ♀ n=7 71 years 48% ♀*

Pregabalin vs. placebo

Stanley et al. (1996)

Community, multicentre, USA/Europe Community, USA

0% buspirone 0% sertraline 27% clinical 27% control

Buspirone vs. sertraline

CBT/PC vs. Enhanced UC CBT vs. WL

CBT vs. DG

12 group sessions

6 months

No

↓ 20% in 3/4 of OM

31% clinical 31% control

6/26 clinical 6/26 control

27

MP vs. Enhanced CT

12 individual sessions 12 individual sessions

No

No

Ø

N/A

25

6 months

No

Ø

20% MP ECT not stated 0% ACC 22% CBT

N/A

26

ACT vs. CBT

CCDAN, Cochrane Collaboration Depression, Anxiety and Neurosis; OC, outcome measures; I/MI, improved/much improved; CBT, cognitive-behavioral therapy; MM, medical management; ER, extended release; WL, waiting list; APT, attention process training; SP, supportive psychotherapy; MCC, minimal contact control; PC, primary care; UC, usual care; DG, discussion group; MP, modular psychotherapy; CT, community treatment; ACT, acceptance and commitment therapy; Ø, not stated or not defined. a Abstract of a conference presentation. b This paper reported two independent trials (standard and enhanced CBT). c Only if it was currently acute. d This paper reported data on three groups (CBT vs. waiting list vs. discussion group), CBT group results are presented twice. * Average age and percentage of female participants were reported for the entire sample together. ** Study did not specifically address older adults; instead, sample was composed by patients who developed MDD and GAD after stroke.

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

Authors (year)

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

7

%

Study ID

OR (95% CI)

Weight

Bresolin et al., 1988

0.20 (0.07, 0.60)

10.04

Frattola et al., 1992

0.18 (0.04, 0.80)

7.33

Subtotal (I-squared = 0.0%, p = 0.897)

0.19 (0.08, 0.46)

17.37

Davidson et al., 2008

0.50 (0.18, 1.37)

10.74

Katz et al., 2005

0.53 (0.27, 1.05)

13.56

Kimuna et al., 2003

0.12 (0.02, 0.69)

6.17

Lenze et al., 2005

0.17 (0.04, 0.75)

7.39

Lenze et al., 2009

0.62 (0.34, 1.12)

14.24

Subtotal (I-squared = 21.4%, p = 0.278)

0.46 (0.29, 0.73)

52.10

Eriksson et al., 2008

0.14 (0.09, 0.22)

15.61

Montgomery et al., 2008

0.62 (0.37, 1.03)

14.92

Subtotal (I-squared = 94.8%, p = 0.000)

0.30 (0.07, 1.25)

30.53

0.32 (0.18, 0.54)

100.00

Benzodiazepine

. Antidepressant

. Other

. Overall (I-squared = 74.8%, p = 0.000) NOTE: Weights are from random effects analysis .1

1

Favours intervention

10

Favours control

Fig. 2. Forest plot for the pharmacological trials, by drug class.

(OR = 0.46, 95% CI: 0.29, 0.73, z = 3.32, p < .001) exhibited statistically significant treatment effects. Psychotherapeutic trials were more homogeneous (Q = 18.07, d.f. = 10, p = .05; I2 = 45%, p = .05), with a pooled odds ratio that favored intervention of 0.33 (95% CI: 0.17, 0.66, z = 3.15, p < .01). There were significant results favoring the intervention when a waiting list (OR = 0.12, 95% CI: 0.04, 0.38, z = 3.58, p < .001), and care as usual/minimal contact (OR = 0.24, 95% CI: 0.09, 0.67, z = 2.73, p < .01) were used as the control condition, but not when an active control condition was employed (OR = 0.75, 95% CI: 0.30, 1.89, z = 0.61, p = .54) or when psychotherapy was used in both arms (OR = 0.76, 95% CI: 0.04, 13.35, z = 0.19, p = .85). The meta-analysis was repeated using only participants who finished treatment, thus not taking dropouts into account. As expected, treatment effects improved for all trials that had reported dropout rates, with a pooled odds ratio of 0.27 (95% CI: 0.16, 0.47, z = 4.74, p < .001) for the pharmacological trials and 0.30 (95% CI: 0.14, 0.64, z = 3.07, p < .001) for the psychotherapeutic trials. An influence analysis indicated that when each study was omitted one at a time no overall significant differences were found, except for Eriksson et al. (2008), as the pooled treatment effects for pharmacological trials decreased to 0.43 (95% CI: 0.29, 0.62) when this particular trial was excluded, which means that treatment effects were worse when this trial was excluded. Publication bias analyses were undertaken, with psychotherapeutic trials being combined regardless of the control condition employed. Begg’s ranked correlation method indicated publication bias for pharmacological (b = −1.30, 95% CI: −2.60, 0.01, p = .05) but not psychotherapeutic (b = 0.21, 95% CI: −1.24, 1.66, p = .75) trials. Visual inspection of the funnel plots (Figs. 4 and 5) also indicated asymmetry for the pharmacological trials. Meta-regression analyses were conducted to assess the impact of trial characteristics on treatment effects (results not

tabulated). There were no significant results for the year the study was conducted, mean age of participants, length of the intervention, the presence of comorbid depression, and study quality score. For psychotherapeutic trials there were no significant results for the intervention modality (individual or group). 4. Discussion Pooled results for pharmacological trials and psychotherapeutic trials that used a waiting list or minimal contact condition demonstrate efficacy for both approaches for the treatment of GAD in older adults. However, no significant pooled treatment effects could be demonstrated for psychotherapeutic trials that used an active control condition (e.g. a discussion group) or compared one form of psychotherapy with another. Our findings were obtained using a secondary intent-to-treat analysis, which categorized all participants who dropped out from a study at any time after randomization as non-responders. The systematic exclusion of participants who are randomized but do not finish the intervention from the analysis creates an obstacle to the proper estimation of treatment effects (Hollis & Campbell, 1999), as often those who drop out have more severe symptoms. Furthermore, dropout rates might be indicative of detrimental aspects, such as side effects, thus providing additional information regarding the suitability of the treatment for the specified population. In the present analysis we did not differentiate reasons for drop out, which might be seen as a limitation as there are likely to be differences between those who quit a study due to side effects (e.g., Montgomery et al., 2008) and those, for example, who withdraw due to conflict with other group members (Stanley et al., 1996). Nevertheless, with this approach we intended to overcome the drawback imposed by just analyzing

8

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

Study ID Waiting list Wetherell et al., 2003 WL Mohlman et al., 2003 ECBT Mohlman et al., 2003 CBT Mohlman & Gorman, 2005 Subtotal (I-squared = 0.0%, p = 0.889) . Usual care Stanley, Hopko et al., 2003 Stanley, Wilson et al., 2009 Stanley, Beck et al., 2003 Subtotal (I-squared = 39.7%, p = 0.190) . Active control Gorenstein et al., 2005 Wetherell et al., 2003 DG Subtotal (I-squared = 0.0%, p = 0.533) . Psychotherapy both arms Mohlman, 2008 Stanley et al., 1996 Subtotal (I-squared = 62.3%, p = 0.103) . Overall (I-squared = 44.7%, p = 0.054)

OR (95% CI)

% Weight

0.15 (0.02, 1.37) 0.06 (0.00, 0.79) 0.21 (0.02, 2.18) 0.09 (0.01, 0.86) 0.12 (0.04, 0.38)

6.80 5.15 6.20 6.68 24.83

0.04 (0.00, 0.83) 0.42 (0.20, 0.90) 0.16 (0.04, 0.61) 0.24 (0.08, 0.67)

4.15 18.04 12.17 34.36

0.56 (0.15, 2.08) 1.00 (0.28, 3.63) 0.75 (0.30, 1.89)

12.43 12.70 25.13

0.11 (0.00, 3.35) 2.26 (0.59, 8.64) 0.76 (0.04, 13.35)

3.42 12.26 15.68

0.33 (0.17, 0.66)

100.00

NOTE: Weights are from random effects analysis .1 1 10 Favours intervention Favours control

Fig. 3. Forest plot for the psychotherapy trials, by comparison condition.

data on participants who finished the study, which increases the risk of a type I error. Overall, treatment effects were better for psychotherapeutic trials that used a passive control condition, either waiting list or minimal contact/care as usual, when compared with pharmacological trials. Positive results obtained by the control group in pharmacological trials are partially explained by the placebo effect and the positive expectations underlying it, which trigger

metabolic changes that mimic the therapeutic effects of medication (Mayberg et al., 2002). Older adults participating in pharmacological trials believed they were receiving treatment, whereas those in psychotherapeutic trials presumably did not. We demonstrated a slightly higher pooled treatment effect for pharmacotherapy when compared with psychotherapy for late life anxiety, corroborating previous findings (Pinquart & Duberstein, 2007). Notwithstanding the significant treatment effects obtained by pharmacological

Begg's funnel plot with pseudo 95% confidence limits

Begg's funnel plot with pseudo 95% confidence limits 1

2 0

LogOR

LogOR

0 -1

-2 -2

-4

-3 0

.5

s.e. of: LogOR Fig. 4. Funnel plot for pharmacological trials.

1

0

.5

1

1.5

s.e. of: LogOR Fig. 5. Funnel plot for psychotherapeutic trials.

2

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

trials, it is also relevant to consider the negative outcomes that might result from this type of intervention, particularly side effects and drug–drug interactions (Doucet et al., 1996; Secoli, Figueras, Lebrao, de Lima, & Santos, 2010), and impact on functional limitations (Ried, Johnson, & Gettman, 1998). It is also difficult to judge from a short pharmaceutical trial whether beneficial effects are likely to be enduring, as non-adherence is a well-recognized problem. In addition, discontinuation trials are needed to determine the necessary duration of drug treatment. Curiously, we found no intervention trials for late-life GAD in which drug treatment was combined with psychological treatment, although this approach might well have merit and some research groups have been exploring it (Gorenstein & Papp, 2007). A recently published open label pilot study indicated that modular CBT enhanced the therapeutic effects of an antidepressant, significantly reducing both anxiety symptoms and pathological worry (Wetherell, Stoddard, et al., 2011). Another possible approach is to implement controlled trials of comparative efficacy of psychotherapeutic and pharmacological trials, as we identified only one study that compared the efficacy of CBT with that of an SSRI in late life anxiety disorders, such as GAD, panic disorder and agoraphobia (Schuurmans et al., 2006). A potentially relevant issue that should be discussed concerns the fact that all trials reported in this review employed outcome measures that had not been purposively developed to assess anxiety symptoms in older people. As previous studies have identified age effects on reporting of anxiety and depression symptoms (Brenes et al., 2008), it might be that the use of measures that were specifically designed to measure anxiety symptoms in older adults (e.g., Pachana et al., 2007; Segal, June, Payne, Coolidge, & Yochim, 2010), would have lead to more reliable and valid results. A final question that should be specifically addressed when intervening with anxious older adults is to what extent the presence of cognitive decline interferes with the clinical outcome. Mohlman and Gorman (2005) assessed participants according to their cognitive functioning, finding that the likelihood of responding to treatment for GAD was lower for those with executive dysfunction at both baseline and post-treatment. On the other hand, those participants who were considered to have executive dysfunction at baseline but recovered during the 13-week trial also achieved satisfactory response rates in their anxiety symptoms. The small number of participants involved precluded further analysis, but these results highlight the importance of taking other factors into account, when intervening in GAD in older adults. Psychotherapy was a more effective intervention for late-life GAD than waiting list, usual care or minimal contact conditions, but the effect was lost when other active conditions were employed as comparators, such as a discussion group (Wetherell et al., 2003) or medical management (Gorenstein et al., 2005). Caution is required when interpreting these results, as there were relatively few studies and they were likely to have been underpowered to detect superiority of one effective psychological treatment over another. An earlier meta-analysis reported that CBT was superior to an active condition or another type of psychotherapy for the treatment of GAD in adults but not in older adults (Hunot, Churchill, de Lima, & Teixeira, 2007). Furthermore, CBT failed to prove to be more effective than an active control condition or another type of psychotherapy for the treatment of late-life anxiety, whereas relaxation training obtained superior results (Thorp et al., 2009). Taken together, these results suggest at least the possibility that older adults with GAD might benefit more than younger adults from non-specific non-pharmacological interventions, including those provided in a group setting (Wetherell et al., 2003). As older adults seem to be more reluctant to seek help from mental health professionals (De Beurs et al., 1999) and to drop out of treatment due to

9

perceived stigma (Sirey et al., 2001), an intervention that follows a more naturalistic structure might be more successful with this age group. For instance, Arean et al. (2002) found that although older adults were reluctant about participating in group therapy, they were willing to attend psychoeducational classes. Furthermore, psychotherapy was selected as the preferred treatment by the majority of older adults who answered a survey about anxiety treatment (Mohlman, in press). Alternatively, effects obtained with the active control conditions might be explained by age-related factors, such as lower levels of overall social interaction experienced by the older adults, who respond to the stimulation given by the active condition. What seems to be established is that GAD in older adults is unlikely to remit without an intervention of some sort, and although some symptomatic improvement is possible even when waiting for treatment (e.g., Wetherell et al., 2009), potential gains are significantly higher when an intervention is used (Wetherell et al., 2003). Some limitations should be acknowledged, involving the inclusion criteria we employed, the heterogeneity of the available clinical trials, and the analyses performed. First, we established tight inclusion criteria that excluded several studies and resulted in a relatively small sample of studies. Nevertheless, by only including controlled studies that used formal diagnostic criteria we aimed to increase the quality of the included trials and hence the reliability of our findings. Despite the apparent absence of a publication bias for the psychotherapeutic trials, the funnel plot is a somewhat limited technique (Lau, Ioannidis, Terrin, Schmid, & Olkin, 2006) and caution is required when interpreting these results. Another limitation concerns the clinical heterogeneity between trials, a result of their differing sample sizes and intervention types. Statistical heterogeneity, as indicated by heterogeneous treatment effects, should also be acknowledged, as this might reduce the generalizability of observed treatment effects (Deeks, Altman, & Bradburn, 2001). In addition, the efficacy of each trial was ascertained by the response rate, definitions of which varied considerably between trials. Even within the same trial different instruments could be used to define response (Stanley et al., 2009). However, response definition was reasonably consistent within trial type (i.e., pharmacological and psychotherapeutic). Furthermore, exclusion of participants who did not complete the treatment from the analysis provides a biased estimate of the potential outcomes promoted by the treatment (Hollis & Campbell, 1999). By adopting response rate as our outcome metric we were able to perform secondary intent-to-treat analyses, thus decreasing the likelihood of a type I error and providing a more comprehensive picture of treatment effects. It is also a limitation that cognitive functioning was not uniformly addressed in the included studies. Whereas some studies screened participants for cognitive functioning, excluding those below a certain threshold (e.g., Gorenstein et al., 2005; Kimura et al., 2003; Wetherell et al., 2003), others did not report on cognitive functioning (e.g., Davidson et al., 2008; Katz et al., 2002). Unmeasured cognitive impairment could have interfered not only with the report of anxiety symptoms but also with symptoms itself, as mild cognitive impairment has been found to be associated with increased anxiety (for a review, see Beaudreau & O’Hara, 2008). Also important is that response was defined using both clinician and self-rated measures, which might have implications for the outcome (Nordhus & Pallesen, 2003). The strengths of our study include the comprehensive literature search conducted, the adoption of an intention-to-treat analysis, and the inclusion of both pharmacological and psychotherapeutic trials. Furthermore, we have included only studies that employed diagnostic criteria to diagnose their participants. Taken together, these allowed us to obtain a more precise estimate of current treatment efficacy for GAD in older cohorts.

10

D.C. Gonc¸alves, G.J. Byrne / Journal of Anxiety Disorders 26 (2012) 1–11

Several positive conclusions can be taken from these results. The first and most relevant is that both pharmacological and psychotherapeutic interventions were effective interventions for GAD in older adults. In addition, older adults clearly benefited from active control conditions, such as discussion groups and enhanced usual care. These findings have significant implications for clinical practice, as they might promote the development of intervention models tailored to older people, which will suit their needs more adequately while overcoming some of the stigma and reluctance associated with traditional forms of mental health care. Also relevant is that both psychotherapeutic and pharmacological interventions were still found to be effective in late life GAD, even when participants who did not complete their intervention were included in the analysis. This aspect of the data allows us to be more confident of the potential benefits of GAD treatment in older adults, than we would have been if we had just focused on the results of those who had finished the protocols. A final positive aspect is the increasing number of controlled trials specifically designed to intervene in late life GAD. All but one of the psychotherapeutic trials was conducted in the past decade. Furthermore, there was a positive and significant association between the publication year and the quality of the study. Despite this significant quantitative and qualitative increase, the body of knowledge is still scarce and more and larger trials are required. Several questions are still unanswered and require further research. For instance, it would be interesting to explore further what are the combined effects of pharmacology and psychotherapy in older adults with GAD. Another enticing hypothesis is to understand to what extent the oldest of the old also benefit from GAD intervention, or whether the existing intervention models provide benefits to older adults with cognitive decline that also present clinically significant anxiety symptoms. Role of funding source Daniela Gonc¸alves was supported by a scholarship from the Fundac¸ão para a Ciência e Tecnologia, Portugal (SFRH/BD/30226/2006) and an anonymous benefactor. Gerard Byrne was supported by grants from the National Health and Medical Research Council (456182), the Alzheimer’s Association (Chicago) (IIRG-07-59015) and the Royal Brisbane and Women’s Hospital Research Foundation. Conflict of interests None to declare. References Arean, P. A., Alvidrez, J., Barrera, A., Robinson, G. S., & Hicks, S. (2002). Would older medical patients use psychological services? Gerontologist, 42(3), 392–398. Beaudreau, S. A., & O’Hara, R. (2008). Late-life anxiety and cognitive impairment: a review. American Journal of Geriatric Psychiatry, 16(10), 790–803. Beaudreau, S. A., & O’Hara, R. (2009). The association of anxiety and depressive symptoms with cognitive performance in community-dwelling older adults. Psychology and Aging, 24(2), 507–512. Beekman, A. T. F., Bremmer, M. A., Deeg, D. J. H., van Balkom, A. J. L. M., Snut, J. H., de Beurs, E., et al. (1998). Anxiety disorders in later life: a report from the Longitudinal Aging Study Amsterdam. International Journal of Geriatric Psychiatry, 13(10), 717–726. Begg, C. B., & Mazumdar, M. (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics, 50(4), 1088–1101. Brenes, G. A., Guralnik, J. M., Williamson, J. D., Fried, L. P., Simpson, C., Simonsick, E. M., et al. (2005). The influence of anxiety on the progression of disability. Journal of the American Geriatrics Society, 53(1), 34–39. Brenes, G. A., Knudson, M., McCall, W. V., Williamson, J. D., Miller, M. E., & Stanley, M. A. (2008). Age and racial differences in the presentation and treatment of generalized anxiety disorder in primary care. Journal of Anxiety Disorders, 22(7), 1128–1136.

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