Antidepressants for treating depression in dementia
Abstract
Background
The use of antidepressants in dementia accompanied by depressive symptoms is widespread, but their clinical efficacy is uncertain. This review updates an earlier version, first published in 2002.
Objectives
To determine the efficacy and safety of any type of antidepressant for patients who have been diagnosed as having dementia of any type and depression as defined by recognised criteria.
Search methods
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register, on 16 August 2017. ALOIS contains information on trials retrieved from databases and from a number of trial registers and grey literature sources.
Selection criteria
We included all relevant double‐blind, randomised trials comparing any antidepressant drug with placebo, for patients diagnosed as having dementia and depression.
Data collection and analysis
Two review authors selected studies for inclusion and extracted data independently. We assessed risk of bias in the included studies using the Cochrane 'Risk of bias' tool. Where clinically appropriate, we pooled data for treatment periods up to three months and from three to nine months. We used GRADE methods to assess the overall quality of the evidence.
Main results
We included ten studies with a total of 1592 patients. Eight included studies reported sufficiently detailed results to enter into analyses related to antidepressant efficacy. We split one study which included two different antidepressants and therefore had nine groups of patients treated with antidepressants compared with nine groups receiving placebo treatment. Information needed to make 'Risk of bias' judgements was often missing.
We found high‐quality evidence of little or no difference in scores on depression symptom rating scales between the antidepressant and placebo treated groups after 6 to 13 weeks (standardised mean difference (SMD) ‐0.10, 95% confidence interval (CI) ‐0.26 to 0.06; 614 participants; 8 studies). There was probably also little or no difference between groups after six to nine months (mean difference (MD) 0.59 point, 95% CI ‐1.12 to 2.3, 357 participants; 2 studies; moderate‐quality evidence). The evidence on response rates at 12 weeks was of low quality, and imprecision in the result meant we were uncertain of any effect of antidepressants (antidepressant: 49.1%, placebo: 37.7%; odds ratio (OR) 1.71, 95% CI 0.80 to 3.67; 116 participants; 3 studies). However, the remission rate was probably higher in the antidepressant group than the placebo group (antidepressant: 40%, placebo: 21.7%; OR 2.57, 95% CI 1.44 to 4.59; 240 participants; 4 studies; moderate‐quality evidence). The largest of these studies continued for another 12 weeks, but because of imprecision of the result we could not be sure of any effect of antidepressants on remission rates after 24 weeks. There was evidence of no effect of antidepressants on performance of activities of daily living at weeks 6 to 13 (SMD ‐0.05, 95% CI ‐0.36 to 0.25; 173 participants; 4 studies; high‐quality evidence) and probably also little or no effect on cognition (MD 0.33 point on the Mini‐Mental State Examination, 95% CI ‐1.31 to 1.96; 194 participants; 6 studies; moderate‐quality evidence).
Participants on antidepressants were probably more likely to drop out of treatment than those on placebo over 6 to 13 weeks (OR 1.51, 95% CI 1.07 to 2.14; 836 participants; 9 studies). The meta‐analysis of the number of participants suffering at least one adverse event showed a significant difference in favour of placebo (antidepressant: 49.2%, placebo: 38.4%; OR 1.55, 95% CI 1.21 to 1.98, 1073 participants; 3 studies), as did the analyses for participants suffering one event of dry mouth (antidepressant: 19.6%, placebo: 13.3%; OR 1.80, 95% CI 1.23 to 2.63, 1044 participants; 5 studies), and one event of dizziness (antidepressant: 19.2%, placebo: 12.5%; OR 2.00, 95% CI 1.34 to 2.98, 1044 participants; 5 studies). Heterogeneity in the way adverse events were reported in studies presented a major difficulty for meta‐analysis, but there was some evidence that antidepressant treatment causes more adverse effects than placebo treatment does.
Authors' conclusions
The available evidence is of variable quality and does not provide strong support for the efficacy of antidepressants for treating depression in dementia, especially beyond 12 weeks. On the only measure of efficacy for which we had high‐quality evidence (depression rating scale scores), antidepressants showed little or no effect. The evidence on remission rates favoured antidepressants but was of moderate quality, so future research may find a different result. There was insufficient evidence to draw conclusions about individual antidepressant drugs or about subtypes of dementia or depression. There is some evidence that antidepressant treatment may cause adverse events.
PICOs
Plain language summary
Antidepressants for treating depression in dementia
Review question
We reviewed the evidence about the effect of antidepressants on depression in people with dementia.
Background
Depression can be hard to recognise in people with dementia, but there is evidence that it is common and associated with increased disability, poorer quality of life, and shorter life expectancy. Many people with dementia are prescribed antidepressants to treat depression, but there is uncertainty about how effective this is.
This review updates an earlier version, first published in 2002.
Search date
We searched up to August 2017 for relevant studies.
Study characteristics
We found ten studies with 1592 people to include in the review. On average, the studies lasted only 12 weeks, although one study ran for nine months. Each of them used a set of formal criteria to diagnose both depression and dementia and compared an antidepressant against a dummy pill (placebo).
The older studies used more old‐fashioned antidepressants (imipramine, clomipramine, and moclobemide) and the newer studies used more modern ones, such as venlafaxine, mirtazapine and so‐called SSRI antidepressants (sertraline, fluoxetine, citalopram and escitalopram).
The people taking part in the studies had an average age of 75 and they had mild or moderate dementia. With the exception of two studies, they were being treated as outpatients.
Key results
We found that there was little or no difference in scores on depression rating scales between people treated with antidepressants and those treated with placebo for 12 weeks. The evidence to support this finding was of high quality, which suggests that further research is unlikely to find a different result. There was probably also little or no difference after six to nine months of treatment.
Another way to assess the effect of antidepressants is to count the number of people in the antidepressant and placebo groups who show significant clinical improvement (response) or who recover from depression (remission). There was low‐quality evidence on the number of people showing a significant clinical improvement and the result was imprecise so we were unable to be sure of any effect on this measure. People taking an antidepressant were probably more likely to recover from depression than were those taking placebo (antidepressant: 40%, placebo: 21.7%). There was moderate‐quality evidence for this finding, so it is possible that further research could find a different result.
We found that antidepressants did not affect the ability to manage daily activities and probably had little or no effect on a test of cognitive function (which includes attention, memory, and language).
People taking an antidepressant were probably more likely to drop out of treatment and to have at least one unwanted side effect.
Quality of the evidence
The quality of the evidence varied, mainly due to poorly conducted studies and problems with the relevance of the outcome measures used. This should be taken into consideration when interpreting the different results on depression rating scales and recovery rates, as evidence was of a higher quality for the former than for the latter.
Another major problem is that side effects are very rarely well‐reported in studies.
Therefore, further research will still be useful to reach conclusions that are more reliable and can better help doctors and patients to know what works for whom.
Authors' conclusions
Summary of findings
| Antidepressant treatment compared with placebo for depression in dementia | ||||||
| Patient or population: patients with depression and dementia Settings: outpatient (except Roth 1996, which was mixed in‐ and outpatients) Intervention: antidepressant treatment Comparison: placebo treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Antidepressant | |||||
| Depression endpoint mean scores at 6 to 13 weeks | The standardised depression ratings scale endpoint mean score in the antidepressant group was 0.10 points lower (0.26 lower to 0.06 higher) | 614 | ⊕⊕⊕⊕ high | No evidence of an effect of antidepressants on depression in dementia | ||
| Number of responders (ITT) at 6 to 12 weeks | 377 per 1000 | 509 per 1000 (326 to 690) | OR 1.71 (0.80 to 3.67) | 116 | ⊕⊕⊝⊝ | No evidence of an effect of antidepressants regarding response to treatment for depression in dementia |
| Number of patients with remission (ITT) at 6 to 12 weeks | 217 per 1000 | 415 per 1000 (285 to 559) | OR 2.57 [1.44, 4.59] | 240 | ⊕⊕⊕⊝ | Evidence of a positive effect of antidepressants on remission of depression in dementia |
| Cognitive function endpoint mean scores at 6 to 12 weeks | The MMSE endpoint mean score in the antidepressant group was 0.33 points higher [1.31 lower to 1.96 higher] | (194) | ⊕⊕⊕⊝ | No evidence of an effect of antidepressants on cognitive function in patients with depression and dementia | ||
| Activities of daily living, endpoint values at 6 to 13 weeks | The standardised mean difference in ADL endpoint mean scores in the antidepressant group was 0.05 points lower [0.36 lower to 0.25 higher] | 173 | ⊕⊕⊕⊕ high | No evidence of an effect of antidepressants on ADLs in patients with depression and dementia. | ||
| Number of dropouts at 6 to 13 weeks | 179 per 1000 | 248 per 1000 (189 to 318) | OR 1.51 (1.07 to 2.14) | 836 | ⊕⊕⊕⊝ | Evidence of a negative effect of antidepressants on staying in treatment in patients with depression in dementia |
| Number of patients experiencing at least one adverse event | 384 per 1000 | 492 per 1000 (430 to 553) | OR 1.55 (1.21 to 1.98) | 1073 | ⊕⊕⊕⊝ | Evidence of a negative effect of antidepressants related to side effects in patients with depression and dementia. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). A SMD of 0.2 is often considered to represent a small effect size, 0.5 a moderate effect size and 0.8 a large effect size. | ||||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1The quality of the evidence was downgraded due to indirectness (the definitions of “response” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”) and imprecision (comparison was underpowered due to low number of total number of participants). 2The quality of the evidence was downgraded due to indirectness (the definitions of “remission” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”). 3The quality of the evidence was downgraded due to imprecision (relatively low number of participants and wide confidence intervals). 4 The quality of the evidence was downgraded due to imprecision (the analysis is underpowered; also, the 95% CI around the pooled or best estimate of effect include both little effect and appreciable harm). 5The quality of evidence was downgraded due to selective reporting. | ||||||
Background
Description of the condition
People with dementia are commonly afflicted with depression (Bennet 2014; Leyhe 2017) and depression is associated with increased disability, impaired quality of life, and higher mortality (Black 2012; Diniz 2013; Vaughan 2015).
However, both depression and dementia are concepts with nebulous boundaries. Depressive illness has been conceptualised in dimensional and categorical terms with no consensus about its fundamental nature. When conceptualised dimensionally, depression's various presentations are explained by their position on a continuum of increasing severity. When conceptualised categorically, depressive illness is sub‐grouped into discrete entities such as melancholic or non‐melancholic depression and anxious depression (Parker 2000). Dementia is a syndrome that may arise from a variety of underlying pathologies, the most common of which are Alzheimer's disease, vascular dementia, and dementia with Lewy bodies.
Given the complex nature of both depression and dementia, understanding the relationship between the two is difficult. Depressive illness in older people can present as 'pseudodementia' and be difficult to distinguish from a dementing illness (Raskind 1998). On the other hand, depression is often associated with deterioration in cognitive functioning which is sometimes not completely reversible with treatment (Abas 1990). Moreover, in older people a history of depression in later life may be associated with an increased risk of subsequently developing a dementing illness (Naismith 2010; Byers 2011; Barnes 2012; Heser 2013; Diniz 2013). Both disorders are common in older people and may therefore be expected to occur together solely by chance.
Because of these complexities, diagnosing depression in patients with dementia can be difficult. Denial and cognitive impairment may compromise self‐report of depressive symptoms by people with dementia. As the dementing illness progresses, the presentation of depression may alter, with non‐verbal manifestations (e.g. demanding behaviour, clinging) being more apparent than cognitive features (Vida 1994). Moreover, neurovegetative (autonomic) symptoms such as poor concentration and anhedonia (reduction in or complete lack of ability to enjoy activities the person usually finds enjoyable) are features of both depression and dementia. Not surprisingly, there is no consensus on how best to diagnose depression in demented patients. Depression symptom scales may overestimate, whereas structured diagnostic interviews may underestimate, the prevalence of depression in people with dementia. Only one instrument — the Cornell Scale for Depression in Dementia (CSDD, Alexopoulos 1988) — has been specifically developed for use in a population with dementia. Given the complexity of the issues impinging on accurate diagnosis, it is not surprising that estimates of the incidence and prevalence rates of depression in patients with dementia vary between 0% and 86%. Larger studies using standardised criteria for major depressive disorder in Alzheimer's disease provide estimates of prevalence at 10% to 20% (Loreck 1993).
Description of the intervention
Drugs licensed as antidepressants are a heterogeneous group. They are commonly described as falling into a number of classes with different mechanisms of action, although the various classes are generally reported to be of similar efficacy (Anderson 2000; Williams 2000). However, different drugs or classes of drugs may vary in their efficacy or safety in the depression of dementia, or may be preferentially effective in particular subtypes of dementia.
The oldest class of antidepressants is the tricyclic antidepressants (TCAs), including drugs such as amitriptyline, imipramine, clomipramine and nortriptyline. As a class, they are associated with side effects that are potentially more problematic for older than for younger patients. In particular, their anticholinergic properties are associated with a negative impact on cognition (Settle Jr 1998). Other problematic anticholinergic effects would include increased intra‐ocular pressure, urinary retention, dry mouth, and constipation. Due to their anti‐adrenergic side effects, they can also cause postural hypotension (Glassman 1981), and dizziness, thereby increasing the risk of falls. A second class of antidepressants, the selective serotonin reuptake inhibitors (SSRIs), is now more widely used for older people. SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. These drugs have a different range of side effects, most notably nausea and vomiting, agitation, anxiety, indigestion, diarrhoea or constipation, loss of appetite and weight loss, dizziness, blurred vision, dry mouth, excessive sweating, insomnia or drowsiness, headaches, and sexual side effects. However, they have less marked anticholinergic and anti‐adrenergic properties and therefore may be less likely to cause confusion or falls (Avorn 1998). Other antidepressant drug classes include selective serotonergic and noradrenergic reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine, tetracyclic anti‐depressants such as trazodone and maprotiline, and the reversible monoamine oxidase inhibitors (MAOIs), such as moclobemide. Another often used example of the newer antidepressants is the alpha2‐antagonist mirtazapine.
Why it is important to do this review
Dementia with depression is a common and important clinical problem. A recent Cochrane Review of psychological treatments for depression in dementia found evidence for benefit, but it was poor‐quality, heterogeneous evidence (Orgeta 2014). The use of antidepressants for patients with dementia accompanied by depressive symptoms is widespread, but their clinical efficacy is uncertain. This uncertainty is due in part to the difficulties of interpreting the results of clinical trials. Many of the individual trials of antidepressants have been too small to provide precise estimates of the benefits that might realistically be expected. Combining the information from all appropriate trials may provide a better estimate of the likely effects of treatment.
Objectives
To determine the efficacy and safety of any type of antidepressant for patients who have been diagnosed as having dementia of any type and depression as defined by recognised criteria.
Methods
Criteria for considering studies for this review
Types of studies
We considered all identified relevant double‐blind, randomised, placebo‐controlled trials of longer than four weeks' duration. Trials in which the allocation to treatment or placebo was not random, or in which treatment allocation was not concealed, were excluded (Altman 1999).
Types of participants
Inclusion criteria
To ensure participants of included trials were comparable, subjects were required to meet accepted diagnostic criteria. We included trials involving participants with dementia as diagnosed by accepted criteria such as DSM (APA 1987), NINCDS‐ADRDA (McKhann 1984) and ICD‐10 (WHO 1992), with a coexisting depressive illness as diagnosed by similarly accepted criteria. Participants could be of either sex and of any age.
Exclusion criteria
We excluded studies of patients with dementia suffering from emotional disorders or behavioural problems, but falling short of a diagnosis of depression (as diagnosed by recognised criteria).
Types of interventions
Inclusion criteria
Any antidepressant medication listed in the British National Formulary number 73, 2017 (see Electronic searches for list of antidepressants) compared with placebo. There was no minimum dose requirement for inclusion.
Exclusion criteria
We excluded trials of euphoriants (e.g. amphetamines), adjuvants (e.g. lithium), combination treatments (e.g. 'Motipres'), studies of other drug classes not generally regarded primarily as antidepressants (e.g. antipsychotics), and agomelatine, which is contra‐indicated in dementia.
Types of outcome measures
The outcomes of interest were as follows (Table 1 summarises the outcome measures analysed in this paper).
| Outcome measure | Abbreviation | Reference | Type of measure | Brief description | Used in |
| Depression rating scales | |||||
| Hamilton Depression Rating Scale | HAMD | depressive symptom levels | Clinician‐rated, multiple choice rating scale of depressive symptom severity designed to be sensitive to change with treatment in the general adult population. | ||
| Cornell Scale for Depression in Dementia | CSDD | depressive symptom levels | For the diagnosis of depression in patients with a dementia syndrome administered by a clinician. It takes 20 minutes with the carer and 10 minutes with the patient. The scale has 19 items, rated on a 3 point scale: absent, mild or intermittent and severe, based on the week prior to the interview. | ||
| Montgomery Asberg Depression Rating Scale | MADRS | depressive symptom levels | A 10‐item clinician‐rated diagnostic questionnaire to measure the severity of depressive symptomatology in mood disorders. | ||
| Geriatric Depression Scale | GDS | depressive symptom levels | A 30‐item, self‐report assessment used to identify depression in the elderly. The simple response format (yes/no questions) makes it more suitable for use in those with cognitive impairment. | ||
| Cognitive measure | |||||
| Mini‐mental State Examination | MMSE | level of cognitive functioning | A 30‐point clinician‐administered cognitive test for cognitive impairment, assessing orientation, concentration, memory, language, and visuo‐spatial function. Higher scores indicate better functioning. | All included studies | |
| Activities of daily living | |||||
| Psychogeriatric dependency rating scales ‐ ADL subscale | PGDRS‐ADL | need for assistance with functional abilities | Physical capacity consists of 7 sub‐categories. Higher scores indicate more disability. | ||
| Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living Scale | ADCS‐ADL | functional ability | Informant‐based, last 4 weeks. Higher score indicates better performance. | ||
| Functional Independence Measure | FIM | need for assistance with functional abilities | 18 items on self‐care, sphincter control, mobility, locomotion, communication, social cognition. Higher scores indicate more disability. | ||
| Older American Resources and Services | OARS‐ADL | functional ability | An 14‐item assessment for physical function, including bathing, dressing, grooming, and continence, relying on self report. Higher scores indicate better functioning. | ||
| Seoul‐Instrumental Activities of Daily Living | SIADL | instrumental everyday activities | A 15‐item instrument to assess complex functions of daily living, with a total score from 0 to 45. Higher scores reflect worse function. | ||
Primary outcomes
Effect on depression (measured by rating scales, and by rates of response or remission defined according to clear criteria).
Secondary outcomes
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Effect on cognitive function (measured by validated psychometric tests).
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Effect on activities of daily living (measured by validated rating scales).
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Effect on quality of life (measured by validated rating instruments).
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Tolerability (measured by withdrawal from trial).
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Safety (measured by the incidence of adverse effects).
Search methods for identification of studies
Electronic searches
We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 16 August 2017. The search was done on a tag used in ALOIS for studies in which the following antidepressant terms have been used: antidepressant, amitriptyline, lentizol, tryptizol, triptafen, amoxapine, asendis, clomipramine, anafranil, dothiepin, perothiaden, doxepin, sinequan, imipramine, tofranil, lofepramine, gamanil, nortriptyline, allegron, protriptyline, concordin, trimipramine, surmontil, maprotiline, ludiomil, mianserin, mirtazapine, zispin, trazodone, molipaxin, viloxazine, vivalan, phenelzine, nardil, isocarboxazid, tranylcypromine, parnate, moclobemide, manerix, fluoxetine, prozac, citalopram, cipramil, fluvoxamine, faverin, paroxetine, seroxat, sertraline, lustral, nefazadone, dutonin, venlafaxine, efexor, flupenthixol, depixol, fluanxol, reboxetine, edronax, tryptophan, optimax, escitalopram, cipralex, dosulepin, dothapex, prepadine, and vortioxetine.
ALOIS is maintained by the Information Specialist for the Cochrane Dementia and Cognitive Improvement Group and contains studies in the areas of dementia prevention, dementia treatment and cognitive enhancement in the healthy. The studies are identified from:
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monthly searches of a number of major healthcare databases: MEDLINE, Embase, Cinahl, PsycINFO and Lilacs;
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monthly searches of a number of trial registers: UMIN (Japan's Trial Register); ICTRP/the WHO portal (which covers ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register; the German Clinical Trials Register; the Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others);
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quarterly search of the Cochrane Library’s Central Register of Controlled Trials (CENTRAL);
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six‐monthly searches of a number of grey literature sources: ISI Web of Knowledge Conference Proceedings; Index to Theses; Australasian Digital Theses.
To view a list of all sources searched for ALOIS, see About ALOIS on the ALOIS website.
Details of the search strategies used for the retrieval of reports of trials from the healthcare databases, CENTRAL and conference proceedings can be viewed in the ‘methods used in reviews’ section within the editorial information about the Dementia and Cognitive Improvement Group.
Additional searches were performed in many of the sources listed above to cover the timeframe from the last searches performed for ALOIS to ensure that the search for the review was as up‐to‐date and as comprehensive as possible. The search strategies used can be seen in Appendix 1.
Searching other resources
We consulted a number of experts in old age psychiatry. We also asked the medical information departments of major pharmaceutical companies to search databases and their records for trials involving their products. In addition, we searched reference lists of retrieved studies and review articles.
Data collection and analysis
Selection of studies
A single review author (for the first edition: JB [see Contributions of authors for full names], for the current revision: RD) discarded irrelevant citations identified by searches, based on the title of the publication and its abstract. If there was any suggestion that an article could be relevant, it was retrieved for further assessment. Two review authors (first edition: JB and JSB, current revision: RD and TD) then independently selected the trials for inclusion in the review from the culled citation list.
Data extraction and management
For the original review, data were independently extracted by two review authors (JB, JSB) and cross‐checked. Any discrepancies were discussed and adjudicated by a third reviewer (TD). For the current revision, data were extracted by the first author (RD). Data were sought on every participant for each outcome measure. To allow an intention‐to‐treat analysis, we sought data irrespective of compliance, whether or not the participant was subsequently deemed ineligible, or otherwise excluded from treatment or follow‐up.
If ordinal scale data appeared to be approximately normally distributed, or if the analysis that the investigators performed suggested that parametric tests were appropriate, then we treated the outcome measures as continuous data. Where the outcome measure was a continuous variable or ordinal variable (such as psychometric test scores, clinical global impression scales, functional and quality of life scales) we extracted summary statistics, including means, standard deviations (SDs) and number in each treatment group, for the final assessment score (corrected for baseline) and the change in score from baseline (i.e. pre‐randomisation or randomisation) to the final assessment for each study. For dichotomous outcomes, the statistics extracted from each study were the numbers in each treatment group and the numbers in each endpoint category for each treatment group. Where dichotomous data were missing, the participants were assumed to have suffered the least favourable outcome. In studies where a cross‐over design was used, only data from the first treatment period were included.
If trial results were reported as medians and interquartile ranges, we calculated SDs using the interquartile range (IQR) to provide the appropriate data to combine the study with other studies.
When two different antidepressants were compared against placebo (Banerjee 2011), we divided the control group where relevant into two groups approximately evenly among the comparisons, with the means and SDs left unchanged. Where it was the only option, we merged the two treatment groups into one (antidepressant efficacy at three to nine months).
Assessment of risk of bias in included studies
We assessed included trials for risk of bias using the tool in theCochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (Higgins 2011). We judged whether each trial was at high, low or unclear risk of bias in each of six domains: sequence generation, concealment of allocation, blinding, completeness of outcome data, selective reporting, and funding source.
Measures of treatment effect
For binary outcome data, we calculated the odds ratio for each trial, and then a pooled odds ratio across appropriate groups of trials (using Mantel‐Haenszel methods). For continuous variables, we calculated the mean difference between treatment and control when each study in the meta‐analysis used the same outcome measure, or the standardised mean difference when the studies used a variety of outcome measures. We used hazard ratios for time‐to‐event data.
Unit of analysis issues
If a trial included multiple treatment groups, then we combined active treatment groups into one group and control treatment groups into one group to allow a single pairwise comparison.
Some studies assessed outcomes at multiple time points, so we pooled data in ranges (e.g. 6 to 13 weeks and 3 to 9 months) to achieve the best match of time points when combining results with similar data from different studies.
Dealing with missing data
For each study, we noted what approach had been taken to missing data, e.g. imputation, data assumed to be missing at random. We considered how each method may have contributed to a risk of bias. We contacted authors of extracted papers for clarification as required.
Assessment of heterogeneity
We tested for heterogeneity of the treatment effect between the trials in a meta‐analysis using the Chi2 statistic. We quantified inconsistency using I2 and considered that an I2 value of more than 40% might represent moderate heterogeneity.
Assessment of reporting biases
If we had been able to include more than 10 studies in any meta‐analysis, then we would have performed a test for funnel plot asymmetry, looking for small study effects which might indicate publication bias.
Data synthesis
We pooled data from different trials if we considered that the trials were sufficiently similar and it was clinically meaningful to do so. In our primary analyses, we pooled trials of all dementia subtypes and all types of antidepressants. We also preformed a separate analysis of antidepressant efficacy at six to nine months.
For dichotomous efficacy outcomes, we used the Mantel‐Haenszel method, as the study sizes were small. For our tolerability outcomes, we used the Peto odds ratio method, as for these outcomes we had larger samples, the intervention effects were relatively small, and the events were not particularly common. If a Chi2 test and I2 indicated little heterogeneity, we used a fixed‐effect model for meta‐analysis. If there was evidence of heterogeneity of the treatment effect between trials, we either pooled only homogeneous results, or used a random‐effects model (in which case the confidence intervals would be broader than those of a fixed‐effect model).
When combining data provided as median and 95% confidence interval (CI), we used the generic inverse variance method. We used standard error and median difference.
Subgroup analysis and investigation of heterogeneity
Five of the included studies used an SSRI antidepressant (Petracca 2001; Lyketsos 2003; Rosenberg 2010; Banerjee 2011; An 2017), one mirtazapine (Banerjee 2011), and one venlafaxine (de Vasconcelos 2007). These are more modern antidepressants commonly used in this patient group (as opposed to tricyclic antidepressants), so we performed a meta‐analysis on these subgroups. Where it made clinical sense (e.g. when examining tolerability), we also looked at data by antidepressant group, where possible.
Sensitivity analysis
When looking at treatment efficacy as reflected by depression symptom rating scale scores, we also performed a sensitivity analysis only looking at studies that used the Cornell Scale for Depression in Dementia (Lyketsos 2003; Rosenberg 2010; Banerjee 2011; An 2017), an instrument specifically developed to measure depressive symptoms in dementia. As in our main treatment efficacy comparison, some studies only reported completer data, so we carried out a sensitivity analysis looking at intention‐to‐treat data only. We also performed a sensitivity analysis when the majority of individual studies reported results pointing toward the opposite of the result of the meta‐analysis, or when excluding a study was considered to reduce imprecision or inconsistency.
Summary of findings
We used the GRADE system to assess the overall quality of evidence behind the effect estimates for each outcome (Ryan 2016). We downgraded the evidence from 'high‐quality' by one, two, or three levels after considering imprecision in the effect estimate, risk of bias in the included studies, inconsistency between studies, indirectness of evidence, and publication bias. Two review authors (RD and TD) assessed the quality of evidence independently and resolved any disagreements.
We presented the amount and quality of evidence in a 'Summary of findings' table for the following outcomes: depression (symptom score), depression (response rate), depression (remission rate), cognitive function, activities of daily living, dropout rate and incidence of adverse events.
Results
Description of studies
Results of the search
Searches carried out in the previous version of the review can be viewed in Appendix 2.
The searches performed for this update, run in November 2010, May 2012, March 2013, December 2013, March 2014, November 2014, October 2015, July 2016, and August 2017 retrieved a total of 827, 1233, 456, 495, 599, 620, 520, 859, and 1304 results, respectively (Figure 1). The Information Specialist performed a first assessment to discard obviously non‐relevant records and duplicates. This left the author team with 43 (November 2010), 49 (May 2012), 27 (March 2013), 36 (December 2013), 31 (November 2014), 22 (October 2015), 40 (July 2016), and 60 (August 2017) results to further assess, from the last two rounds of which three additional trials were identified (DIADS, Banerjee 2011, and An 2017).
Study flow diagram.
Included studies
See: Characteristics of included studies (Table 2).
| Trial | dementia criteria | depression criteria | number of patients | duration | intervention | mean age | mean MMSE | mean depression rating scale score |
| NINCDS‐ADRDA for AD | three or more from Olin's criteria for depression in AD | 84 | 8 weeks | 5 mg/day of escitalopram, increased 5 mg/day every two weeks, up to a maximum dosage of 15 mg/day | 75.2 (6.9) | 18.85 | CSDD: 11.39 | |
| NINCDS‐ADRDA for probable or possible AD | depression ≥ 4 weeks's duration potentially needing antidepressants; CSDD ≥ 8 | 326 | 39 weeks | sertraline 70 mg/d (target dose: 150 mg/d), mirtazapine 24 mg/d (target dose: 45 mg/d) | 79.3 | 18.1 | CSDD: 12.9 | |
| DSM‐IV for dementia (AD, VD, and mixed) | DSM‐IV major depressive disorder and CSDD | 31 | 6 weeks | venlafaxine (37.5‐131.25 mg/d, mean = 75 mg/d) | 77.6 (6.4) | (range: 10‐24) | MADRS: 24.5 (7.1) | |
| DSM‐III‐R for PDD | DSM‐III‐R 290.21(mildly depressed) | 127 | 8 weeks | maprotiline (25 mg titrated to 75 mg/d, mean max. dose 59 mg/d) | 80 (48‐96) | 15.4 (0‐30) | GDS (median): 8 | |
| NINCDS‐ADRDA for probable AD | DSM‐VI for major depressive episode | 44 | 12 weeks | sertraline (25 mg titrated to 150 mg/d, mean peak dose 113 mg) | 77.7 | 16.9 | Ham‐D: 22.75 | |
| NINCDS‐ADRDA for probable AD | DSM‐III‐R for dysthymia or major depression | 24 | 6 weeks + 6 weeks | clomipramine (25 mg titrated to 100 mg/d) | 72 (7.2) | 21.5 (6.2) | Ham‐D:17.5 (6.0) | |
| NINCDS‐ADRDA for probable AD | DSM‐IV criteria for either major or minor depression | 41 | 6 weeks | fluoxetine (10 mg titrated to 40 mg/d) | 70.8 | 23.2 | Ham‐D: 16.5 | |
| DSM‐III for PDD | DSM‐III (major depressive disorder) | 28 | 8 weeks | imipramine (mean dose 83 mg/d) | 72 (8) | 17.5 (5.1) | Ham‐D: 18.9 (3.8) | |
| DSM‐IV for AD | Criteria for depression of AD | 131 | 12 weeks | sertraline 50 mg/d increased to 100 mg/d, mean = 93.1 mg/d) | 77.3 (8.0) | 20.0 (4.6) | CSDD (median): 13 (1st and 3rd quartile: 9, 18) | |
| DSM‐III for dementia | DSM‐III for major depressive episode | 726 | 6 weeks | moclobemide (400 mg/d) | 74.4 (8.5) | 20.2 (4.8) | 24.5 (5.3) | |
| (extension of Rosenberg 2010) | DSM‐IV for AD | Criteria for depression of AD | 131 | 24 weeks | randomised treatment with sertraline for at least partial responders after week 12 | 77.3 (8.0) | 20.0 (4.6) | CSDD (median): 13 (1st and 3rd quartile: 9, 18) |
Ten studies with a total of 1592 participants met the inclusion criteria. The studies were generally of short duration (mode: 6 weeks; mean: 12.7 weeks), although the largest study ran for nearly 10 months (Banerjee 2011). The findings from one study (DIADS‐2) were reported in separate publications, giving results at 12 weeks (Rosenberg 2010), and also after an extension phase at 24 weeks (Weintraub 2010).
All 10 studies stated that the participants met DSM criteria for dementia or NINCDS‐ADRDA criteria for probable Alzheimer's disease. The dementia diagnoses in the trial participants were described in a variety of ways:
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An 2017: "Alzheimer's disease";
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Banerjee 2011: "probable Alzheimer's disease";
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de Vasconcelos 2007: "Alzheimer's disease, vascular dementia, and mixed dementia";
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DIADS‐2 (Rosenberg 2010 and Weintraub 2010): "DSM‐IV dementia due to Alzheimer's disease";
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Fuchs 1993: "primary degenerative dementia";
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Lyketsos 2003: "probable Alzheimer's disease";
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Petracca 1996: "Alzheimer's disease";
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Petracca 2001: "probable Alzheimer's disease";
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Reifler 1989: "primary degenerative dementia of the Alzheimer's type";
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Roth 1996: "dementia".
The mean age of participants who met inclusion criteria in the studies, excluding one study which only reported the median age of 80 years (Fuchs 1993), was between 70.8 and 79.3 years, with an overall mean of 75.37 years.
One Austrian study was conducted among inpatients and nursing home residents (Fuchs 1993). One multinational study included both inpatients and outpatients (Roth 1996). The other studies were conducted in single countries and included only outpatients. The outpatient settings varied, including neurology outpatient clinics in Argentina, specialist memory and other outpatient clinics in the USA and Brazil, and community mental health teams in the UK.
The severity of dementia in the studies varied. The mean Mini Mental State Examination (MMSE) score prior to treatment in those participants who met inclusion criteria for the review was between 16.9 to 23.2 (mean score 19.65). One study, de Vasconcelos 2007, only reported a range of MMSE scores of 10 to 24, and another, Fuchs 1993, reported a median of 20 and no mean scores.
Six studies stated that the participants met DSM criteria for major depression, with one study stating subjects met DSM criteria for either major or minor depression (Petracca 2001). One study required the presence of depression of at least four weeks' duration, assessed as potentially needing antidepressants and scoring eight or more on the Cornell Scale for Depression in Dementia (CSDD), prior to inclusion (Banerjee 2011). In most studies, participants were diagnosed clinically, whereas two studies used a structured clinical interview schedule (Petracca 1996; Petracca 2001). The DIADS‐2 study used specifically adapted Major Depression Criteria. The papers reporting on this study (Rosenberg 2010; Weintraub 2010), do not provide validity data regarding the Major Depression Criteria, but a relevant study, Teng 2008, reported for the criteria set 100% sensitivity and 66% specificity for major and 94% sensitivity and 85% specificity for minor depression, measured against the DSM‐IV diagnosis, which is acceptable.
The older studies used tricyclic antidepressants (TCAs) or related compounds; four used a selective serotonin reuptake inhibitor (SSRI); one used a reversible monoamine oxidase inhibitor; and one a serotonin/noradrenaline reuptake inhibitor. One study had two active treatment arms, an SSRI and a noradrenergic and specific serotonergic antidepressant (NaSSA) one (Banerjee 2011). The doses used in seven studies were within the therapeutic range for the specific medication. However, three studies used lower dose medication (Fuchs 1993; de Vasconcelos 2007; Banerjee 2011, for mirtazapine).
The studies used a variety of outcome measures. Four studies used the Hamilton Depression Rating Scale, and four used the more specific Cornell Scale for Depression in Dementia to measure changes in depression symptom levels after treatment. One study used the Montgomery‐Asberg Depression Rating Scale and another used the Geriatric Depression Scale. All included studies used the Mini‐Mental State Examination to assess changes in cognitive functioning. Only five studies deployed one of four different standardised measures of activities of daily living.
Table 1 summarises the outcome measures included in this review.
Excluded studies
We excluded studies identified by the searches if their subjects did not have both depression and dementia diagnosed by formal criteria, the intervention was not an antidepressant or it was given in combination with another drug, the study was not a treatment trial or a randomised controlled trial, or change in depression was not measured.
Ongoing studies
We are not aware of any ongoing studies.
Risk of bias in included studies
See our 'Risk of bias' assessment of included studies in Figure 2 and Figure 3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Two studies gave adequate descriptions of the randomisation method and allocation concealment and we judged them to be at low risk of bias in both of these domains (Lyketsos 2003; Banerjee 2011). The other studies stated that they were randomised but did not describe the methods used for sequence generation or allocation concealment so we judged the risk of bias to be unclear.
All 10 studies said they were double‐blind but only two reported checking on this. The nature of the placebos was not stated in two studies (Fuchs 1993; An 2017). In seven studies (Reifler 1989; Petracca 1996; Petracca 2001; Lyketsos 2003; de Vasconcelos 2007; Rosenberg 2010; Banerjee 2011), drug and placebo were described as "identical" in appearance, and in one study it was described as "matched" (Roth 1996). With the exception of two studies that explicitly checked whether examiners were able to guess allocation status (Petracca 1996; Rosenberg 2010), there was insufficient information to permit judgement about the integrity of blinding, therefore the risk of bias due to performance or detection bias (or both) was rated as unclear in these studies. Study clinicians correctly guessed allocation status above chance levels in the active treatment group in one study (Rosenberg 2010), therefore we judged this risk of performance bias as high.
Four studies provided intention‐to‐treat data (Fuchs 1993; Lyketsos 2003; DIADS‐2: Rosenberg 2010 and Weintraub 2010; Banerjee 2011), three studies only reported completers' data (Reifler 1989; Petracca 1996; An 2017), and two studies reported both types of data (Petracca 2001; de Vasconcelos 2007). We combined these data in the analyses and carried out sensitivity analyses where we considered this to be appropriate. The attrition rate was very high and unbalanced between groups in three studies (Banerjee 2011; de Vasconcelos 2007; An 2017), therefore we rated the attrition bias as high in these studies. In Weintraub 2010, only 57% of patients were receiving treatment by week 24, therefore we rated the risk of attrition bias as high.
We considered three studies to be at high risk of selective reporting bias (Fuchs 1993; Roth 1996; An 2017). In An 2017, both ITT and per protocol analyses were performed but only the latter was reported. The paper also mentioned response and remission analyses in the methods section, but did not report these. The other two studies reported incomplete data for the depression rating scale scores (Fuchs 1993; Roth 1996).
Most included studies did not publish enough information for us to assess risk of bias related to funding; we considered one study to have low risk of bias (Banerjee 2011), one study to have high risk of bias (Roth 1996), and the rest to have unclear risk of bias.
Effects of interventions
See antidepressant versus placebo comparisons in Data and analyses, and summary of findings Table for the main comparison.
We included 10 included studies with a total of 1592 participants. Two studies published results for trial completers but did not include the numbers in each treatment group who had completed (Fuchs 1993; Roth 1996). Therefore we were only able to use adverse events data from both of these studies. One study had a cross‐over design and we used data from the first treatment period only (Petracca 1996). Only one study used the Montgomery‐Asberg Depression Rating Scale (MADRS) (de Vasconcelos 2007). One study reported outcomes using both the Cornell Scale for Depression in Dementia (CSDD) and the Hamilton Depression Rating Scale (HAM‐D) (Lyketsos 2003); when pooling data from all studies, we used the CSDD data from this study.
We pooled data separately for outcomes reported at 6 to 13 weeks and 24 to 39 weeks (6 to 9 months). Two studies contributed data to both time point analyses (DIADS‐2: Rosenberg 2010; Weintraub 2010, 12 and 24 weeks; Banerjee 2011, 13 and 39 weeks).
Treatment efficacy
The analyses concerning efficacy included eight studies (An 2017; Banerjee 2011; de Vasconcelos 2007; Lyketsos 2003; Petracca 1996; Petracca 2001; Reifler 1989; Rosenberg 2010), with a total of 614 subjects.
Depression (measured by rating scales)
We found that there was little or no effect of antidepressant treatment on depression measured with symptom scales after 6 to 13 weeks of treatment, compared to placebo (standardised mean difference (SMD) ‐0.10, 95% confidence interval (CI) ‐0.26 to 0.06; 614 participants; 8 studies; I2 = 7%; Analysis 1.1; Figure 4). Although this analysis included treatment with different types of antidepressants, heterogeneity was low and we considered the evidence to be of high quality. Two of the studies included in this meta‐analysis only reported completers' data (Reifler 1989; Petracca 1996), therefore we carried out a sensitivity analysis excluding these studies. The result, now based entirely on intention‐to‐treat data, was unchanged and indicated little or no difference between antidepressant and placebo treatment (SMD ‐0.10, 95% CI ‐0.27 to 0.07, P = 0.24). It is of note that the two studies excluded in the sensitivity analysis (Reifler 1989; Petracca 1996), investigated the effect of tricyclic antidepressants (TCAs) (drugs not commonly used in this population).
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.1 Depression endpoint mean scores at 6‐13 weeks.
Two studies assessed outcomes after a longer treatment period: after 24 weeks, DIADS‐2 (Weintraub 2010), and after 39 weeks (Banerjee 2011). Both measured depressive symptoms using the CSDD. We found that there was probably little or no effect of this more prolonged treatment on depressive symptoms (mean difference (MD) 0.59 point, 95% CI ‐1.12 to 2.3, 357 participants; Analysis 1.2). Heterogeneity was low (I2 = 0%), but we considered this moderate‐quality evidence due to methodological limitations, as both studies had a high attrition rate and one study (DIADS‐2) also had a high risk of bias related to blinding.
We looked separately at results from the studies which assessed depressive symptoms after 12 or 13 weeks using the CSDD (Lyketsos 2003; the DIADS‐2 study in Rosenberg 2010; and Banerjee 2011). An analysis of the findings from these three studies indicated little or no benefit from treatment with an antidepressant (MD ‐0.10 point, 95% CI ‐0.99 to 0.78; 433 participants; 3 studies; Analysis 1.2).
In a pooled analysis of the four studies which used the Hamilton Depression Rating Scale (Reifler 1989; Petracca 1996; Petracca 2001; Lyketsos 2003), there was little or no difference between placebo and antidepressant after 6 to 12 weeks of treatment (MD ‐0.85, 95% CI ‐2.65 to 0.95; participants = 134; studies = 4; I2 = 24%; Analysis 1.3).
The only study using the Montgomery‐Asberg Depression Rating Scale, de Vasconcelos 2007, reported no significant difference in mean score changes.
A subgroup analysis of the five studies using a selective serotonin reuptake inhibitor (SSRI) showed little or no difference between the antidepressant and placebo groups (SMD ‐0.13, 95% CI ‐0.33 to 0.07; 400 participants; 5 studies; I2 = 42%; see 1.1.1 in Analysis 1.1). There was moderate heterogeneity in the data, but nevertheless, we considered this overall to be high‐quality evidence.
Depression (measured by rates of response or remission)
We also sought to examine rates of response and remission from depression. "Response" was defined as "partial response" by best clinical judgment rated by two psychiatrists (Lyketsos 2003), 50% or more reduction in HAM‐D scores (Petracca 2001), or a modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (mADCS‐CGI) rating of 2 or less (Weintraub 2010). Data on response to treatment after 6 to 12 weeks came from two studies using an SSRI (Petracca 2001; Lyketsos 2003). There may be a higher response rate among participants on antidepressants than on placebo (odds ratio (OR) 2.42, 95% CI 0.97 to 6.09; 85 participants; 2 studies; I2 = 0%; Analysis 1.4.1; Figure 5), but there is a lot of uncertainty about this result, which is also consistent with little or no effect. We considered this evidence to be low‐quality, due to indirectness (the definitions of “response” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”) and imprecision (comparison was underpowered due to low numbers of participants). A third study, de Vasconcelos 2007, used 50% or more reduction in MADRS scores as a definition of remission as opposed to response, but to be consistent with other studies we also included their data in our meta‐analysis of response rates. When we added this third study (Analysis 1.4), the result remained imprecise with uncertainty about the direction and size of the effect (OR 1.71, 95% CI 0.80 to 3.67; 116 participants; 3 studies; I2 = 13%). Only one study (DIADS‐2: Weintraub 2010) provided longer‐term data on response. The result was imprecise so the effect of antidepressants after 24 weeks was uncertain (OR 1.45, 95% CI 0.72 to 2.92; 131 participants; 1 study; I2 = 0%).
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.4 Number of responders (ITT) at 6‐12 weeks.
"Remission" was defined by the authors of the studies as a HAM‐D score of seven or lower (Petracca 1996), a HAM‐D score of seven or lower and Clinical Global Impression rating of one or two (Petracca 2001), "full response" rated by two psychiatrists' best clinical judgment (Lyketsos 2003), or a mADCS‐CGI rating of two or lower and a CSDD score of six or lower (DIADS‐2: Rosenberg 2010, Weintraub 2010). Although with the exception of the smallest study (Petracca 1996), there was no significant difference in remission rates between the antidepressant and placebo treated groups reported in individual studies, a meta‐analysis indicated that at 6 to 12 weeks remission rates favoured antidepressant over placebo (OR 2.57, 95% CI 1.44 to 4.59; 240 participants; 4 studies; I2 = 0%; Analysis 1.6; Figure 6). We regarded this as moderate‐quality evidence due to indirectness (i.e. definitions of “remission” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”). A subgroup analysis of the SSRI studies indicated that remission rates were higher in the antidepressant group than in the placebo group (OR 2.22, 95% CI 1.20 to 4.12; 216 participants; 3 studies; I2 = 0%; Analysis 1.6), based on evidence graded as low‐quality due to indirectness and imprecision (comparison was underpowered due to low number of participants). Again, only one study (DIADS‐2: Weintraub 2010) provided longer term data and the result was imprecise so the effect of antidepressants on remission after 24 weeks is uncertain (OR 1.75, 95% CI 0.80 to 3.82; 131 participants; 1 study; Analysis 1.7).
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.6 Number of patients with remission (ITT) at 6‐12 weeks.
Cognitive function
Meta‐analyses of cognitive function measured with the Mini Mental State Examination (MMSE) showed that there was probably little or no difference between antidepressant or placebo at weeks 6 to 12, whether the outcome was endpoint mean scores (MD 0.33 point, 95% CI ‐1.31 to 1.96; 194 participants; 5 studies; I2 = 0%; Analysis 1.8) or change in mean scores (MD 0.19 point, 95% CI ‐0.81 to 1.19; 5 studies; Analysis 1.9). This was also true in sensitivity analyses looking at endpoint intention‐to‐treat (ITT) data (Petracca 2001; Lyketsos 2003: MD ‐0.76 point, 95% CI ‐3.78 to 2.27, P = 0.62) or completers‐only data (Reifler 1989; Petracca 1996; Petracca 2001: MD ‐0.34 point, 95% CI ‐3.06 to 2.39; P = 0.81; analysis not presented). We regarded this as moderate‐quality evidence due to imprecision (relatively few participants and wide confidence intervals). There was also no evidence of a difference between groups at six to nine months for endpoint mean scores (MD 1.00 point, 95% CI ‐1.14 to 3.14; 131 participants; 1 study; see Analyis 1.7.2) or change in mean scores (MD ‐0.38 point, 95% CI ‐1.90 to 1.13; 2 studies; Analysis 1.9) on the MMSE.
Activities of daily living
Five studies measured performance of activities of daily living (ADLs) using different scales (Reifler 1989; Petracca 1996; Petracca 2001; Lyketsos 2003; An 2017). We were able to pool data from four studies to estimate a standardised mean difference between groups; we had to exclude the data from Petracca 1996, because they were available only as change‐from‐baseline while the other studies reported endpoint scores. There was little or no difference between antidepressants and placebo as regards ADLs at weeks 6 to 13 (SMD ‐0.05, 95% CI ‐0.36 to 0.25; 173 participants; 4 studies; I2 = 20%; Analysis 1.10, Figure 7). We considered this to be high‐quality evidence. The only study that reported data at six to nine months (Weintraub 2010) did not indicate any difference between groups either.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.10 Activities of daily living, endpoint values at 6‐13 weeks.
Quality of life
We could not pool the results on quality‐of‐life outcomes from two studies (Weintraub 2010; Banerjee 2011), as they reported data in very different formats. Neither study reported any significant difference by treatment group.
Dropouts and adverse effects
Tolerability (measured as withdrawal from trial)
Data from nine studies indicated that participants on antidepressant treatment were probably more likely to drop out of the study over 6 to 13 weeks (OR 1.51, 95% CI 1.07 to 2.14; 836 participants; 9 studies; I2 = 0%; Analysis 1.12; Figure 8). We graded this evidence as moderate‐quality due to imprecision. Subgroup analyses looking at SSRIs, venlafaxine, mirtazapine, and older antidepressants separately found that placebo was consistently favoured, but the results for the individual antidepressants were associated with more uncertainty and in each case were also consistent with little or no difference between groups. There was no clear evidence of a difference between groups after six to nine months (OR 1.25, 95% CI 0.83 to 1.88; 457 participants; 2 studies; Analysis 1.13), on the basis of evidence rated as moderate‐quality due to imprecision.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.12 Tolerability: Number of dropouts at 6‐13 weeks.
Safety (measured by the incidence of adverse effects)
Participants taking an antidepressant were probably more likely to experience at least one adverse event at 6 to 13 weeks (Peto OR 1.55, 95% CI 1.21 to 1.98; 1073 participants; 3 studies; I2 = 26%; Analysis 1.14), although we considered the evidence to be moderate‐quality due to publication bias. This effect was more pronounced with SSRIs and older antidepressants, whilst the Peto OR in the mirtazapine data was not significant. There were statistically significant differences in favour of placebo for numbers of participants experiencing dry mouth (Peto OR 1.80, 95% CI 1.23 to 2.63; 1044 participants; 5 studies; I2 = 55%; Analysis 1.15) and dizziness (Peto OR 2.00, 95% CI 1.34 to 2.98; 1044 participants; 5 studies; I2 = 29%; Analysis 1.18). We rated the evidence for both these outcomes as high‐quality. Subgroup analyses revealed similar patterns with SSRIs and older antidepressants for both outcomes. There were no statistically significant differences found for fatigue (quality of the evidence rated as low due to selective reporting and imprecision; Analysis 1.16) or constipation (quality of evidence rated as moderate due to imprecision; Analysis 1.17).
Data on serious adverse events (SAEs) were reported in a number of the included studies but unfortunately in different formats, therefore they could not be pooled. Banerjee 2011, which looked at data at 13 weeks, reported 15 SAEs in the placebo group, 12 in the sertraline group, and 14 in the mirtazapine group; out of these, 3, 8, and 10 were severe, respectively, suggesting that although the overall number of SAEs did not differ between groups, more of these events were severe in those participants on antidepressants compared with placebo. Over 24 weeks in the DIADS‐2 study (Weintraub 2010), SAEs occurred in 27.3% of participants on sertraline compared with 12.7% of those on placebo. Petracca and colleagues reported serious side effects in one participant who was in the group treated with an antidepressant (Petracca 2001); and in Roth 1996, 27.4% of the adverse events were rated as severe in the placebo group compared with 29% in the moclobemide group (however it should be noted that their "safety" population included both participants with dementia with depressive symptoms and those with depression with cognitive decline). Overall, it seems that SAEs occurred more often in those participants given antidepressants compared to those on placebo.
Discussion
Summary of main results
Meta‐analyses of outcome measures relating to antidepressant treatment efficacy revealed little or no effect of antidepressants on depression rating scale mean scores at 6 to 12 weeks (high‐quality evidence) or at 6 to 9 months (moderate‐quality evidence). There was also no clear evidence of an effect of treatment on the number of responders (low‐quality evidence). We found moderate‐quality evidence favouring antidepressants in the comparison of remission rates at 6 to 12 weeks, but the result at 24 weeks was imprecise and we could not be sure that the difference was maintained.
Subgroup analyses looking at selective serotonin reuptake inhibitors (SSRIs), venlafaxine, mirtazapine, and tricyclic antidepressants (TCAs) separately did not indicate differences between these subgroups. A sensitivity analysis looking at studies which measured depression with the Cornell Scale for Depression in Dementia (CSDD), which is designed specifically to assess depression in dementia, found little or no effect of antidepressants when compared to placebo.
There was little or no difference in measures of cognitive function (Mini Mental State Examination (MMSE) scores) or activities of daily living between antidepressant and placebo groups (moderate‐ and high‐quality evidence, respectively).
Participants taking antidepressants were probably more likely to drop out of treatment and more likely to experience at least one adverse event over 6 to 12 weeks. Patients on antidepressant were significantly more likely to experience dry mouth or dizziness, but not fatigue or constipation.
Overall completeness and applicability of evidence
The process of combining data from differing studies is problematic. The assumption is that the study samples are drawn from similar populations but the validity of this assumption is difficult to assess. The adherence to the inclusion criteria for studies ensures some homogeneity in that all participants included in the review meet recognised criteria for both depression and dementia.
As discussed earlier, the relationship between depression and dementia is complex, and depression is more difficult to diagnose in patients with dementia. DSM criteria for depression include anhedonia and poor concentration, which are both symptoms of dementia. Some studies attempted to take this potentially confounding factor into account when making the diagnosis of depression (Lyketsos 2003; Rosenberg 2010; Banerjee 2011). A further concern is that only one of the depression rating scales used in the included studies was developed for the specific purpose of measuring depression in dementia (CSDD). Other instruments used in the included studies were developed in younger subjects and may underestimate depression in older patients because of the atypical nature of depression in older people (e.g. the Hamilton Depression Scale, HAM‐D). Even where scales are designed specifically for the older population, they may not be reliable in the specific scenario of depression in dementia (e.g. the Geriatric Depression Scale) (Burns 2002). Assessing response to treatment and remission is also fraught with difficulties in these patients.
Depression and dementia are both highly heterogeneous conditions. Patients with mild dementia who are unhappy at the threat to future independence which their diagnosis represents, may be different from those with a MMSE of 15, apathy, anhedonia, low mood and intermittent anxiety. Theoretically, this difference has the potential to obscure potentially useful benefits of antidepressants in patient subgroups. There was no important heterogeneity in our meta‐analysis. However, this might be because all studies examined patients with a wide range of MMSE scores. It should therefore be regarded as absence of evidence rather than evidence of absence.
We only included studies using formal criteria for depression to improve the reliability and clinical applicability of our findings, thereby including the more severe end of the depressive spectrum which is more likely to respond to antidepressant treatment.
It cannot be excluded that adjuvants (e.g. lithium or antipsychotics) or combination treatments (not studied in this review) could show a significant effect in the treatment of patients with depression in dementia.
It is of note that activities of daily living and especially dementia‐specific quality‐of‐life measures have only been used in the more recent studies.
Quality of the evidence
As presented in the 'Risk of bias' and 'Summary of findings' tables, the quality of the evidence for most outcomes was of moderate‐ or low‐quality principally due to risk of bias and imprecision.
The analysis of adverse event data in these studies was particularly difficult due to a number of factors. There was considerable heterogeneity in the reporting of adverse events across the studies in terms of comprehensiveness, mode of ascertainment, and format. Some studies reported all or nearly all side effects and adverse events, some grouped these into systems (e.g. respiratory system, gastrointestinal system, etc.), some only reported serious adverse events, and some a mixture of these. Ideally, figures for all categories should be reported in order that results from different studies (often using different medications) can be meta‐analysed. The studies also differed in terms of whether they relied on spontaneous reporting or various types of questioning. Some reports included the total number of adverse events, others only published the number (or percentages) of participants reporting side effects, or those who withdrew from the study due to adverse events. Tolerability ratings (very good, good, etc.) presented by the investigator appear a subjective measure. Only one study made explicit reference to accepted guidelines in how the authors defined serious adverse events (SAEs) (Rosenberg 2010). They used the Food and Drug Administration definition, i.e. any adverse drug experience occurring at any dose that resulted in any of the following: death, a life‐threatening adverse experience, inpatient hospitalisation or prolongation of existing hospitalisation, or persistent or significant disability/incapacity. Following a set of consistent guidelines on reporting would significantly enhance the reliability of the evidence base.
Potential biases in the review process
It is unfortunate that the results of two of the ten studies (Fuchs 1993, Roth 1996) included in this update could not be included in the efficacy meta‐analysis, as they did not include the numbers in each treatment group who had completed the study. The authors of the studies were contacted and statistical elaboration requested, but for various reasons elaboration did not prove possible. This is of particular regret with regards to Roth 1996, as it was a large multi‐centre study with 476 participants meeting inclusion criteria for the review and the authors reported positive results. It is a limitation of our study that in order to be able to enter the sertraline and mirtazapine arms of Banerjee 2011, we had to split the control group into two groups which remained correlated.
We used endpoint data as opposed to change from baseline, as the latter are often not reported and calculating the standard deviation from the reported data is problematic.
It is also possible that our study has failed to find an effect that really exists (type 2 error). We argue that this possibility is less likely, as we have minimised the amount of data manipulation and simply combined symptom scores; therefore unwitting biases are less likely to have emerged.
Agreements and disagreements with other studies or reviews
Other reviews of this subject have been published. A review by Starkstein and colleagues, Starkstein 2006, drew attention to two individual studies that are also included in our analysis (Roth 1996; Lyketsos 2003), and reported efficacy in the treatment of depression in dementia with sertraline and moclobemide, respectively.
A systematic review by Thompson and colleagues concluded that antidepressants were efficacious (Thompson 2007). This review examined antidepressants in Alzheimer's disease rather than just in dementia as a whole but this difference is unlikely to have been important, as the authors included four of the same studies that we have used here (Reifler 1989; Petracca 1996; Petracca 2001; Lyketsos 2003). The fifth study used by Thompson and colleagues, Magai 2000, was excluded from our review because only 10% of the sample had diagnosed major depression and we felt the validity of the diagnosis of depression was questionable and not comparable with other studies, considering that they had to rely on proxy measures in a patient population much more severely demented than in the other studies included. Proxy measures included cut‐off scores on the Cornell Scale and the Gestalt Depression Scale (Greenwald 1991), and also analysis of facial expression. Thompson and colleagues adopted a different approach, namely to define cases as responders on the basis of a 50% reduction in their depression scores (HAM‐D or other) or as achieving remission (HAM‐D score of less than eight, or equivalent) (Thompson 2007). However, the authors also went on to state that: "Other definitions of depression remission or response were considered if they were deemed clinically valid and (or) relevant". In contrast, we have looked at depression scores as continuous variables as well as examining response and remission. Introducing criteria for response and remission carries the possibility of introducing a bias in favour of treatment (type 1 error). In their narrative review, Farina and colleagues also concluded that antidepressants are not effective for depression (Farina 2017).
Another review, which included the de Vasconcelos and Rosenberg studies (both of which reported lack of efficacy) in addition to the same ones included in the Thompson review, was in accordance with our findings (Nelson 2011). A meta‐analysis by Sephery and colleagues, Sepehry 2012, found a lack of efficacy for antidepressants based on data from five studies. Several other recent reviews also noted the limited evidence and concluded that more studies were needed (Modrego 2010; Saarinen 2010; Haight 2013; Leong 2014; Orgeta 2017).
Our findings are also somewhat different to some other reviews regarding drug safety. The Thompson review reported dropouts from treatment due to all causes and due to adverse events, but did not examine individual symptoms. From this relatively broad approach, they found no significant differences. However, we have analysed data regarding several side effects and found that participants treated with antidepressants experienced significantly more adverse events. It should be noted that three studies that contributed to this analysis were not available to Thompson and colleagues (the Banerjee, de Vasconcelos, and DIADS‐2 studies).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.1 Depression endpoint mean scores at 6‐13 weeks.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.4 Number of responders (ITT) at 6‐12 weeks.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.6 Number of patients with remission (ITT) at 6‐12 weeks.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.10 Activities of daily living, endpoint values at 6‐13 weeks.
Forest plot of comparison: 1 Antidepressant versus placebo, outcome: 1.12 Tolerability: Number of dropouts at 6‐13 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 1 Depression endpoint mean scores at 6‐13 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 2 Cornell Scale for Depression in Dementia (CSDD).
Comparison 1 Antidepressant versus placebo, Outcome 3 Hamilton Depression rating Scale (HDRS).
Comparison 1 Antidepressant versus placebo, Outcome 4 Number of responders (ITT) at 6‐12 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 5 Number of responders (ITT) at 24 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 6 Number of patients with remission (ITT) at 6‐12 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 7 Number of patients with remission (ITT) at 24 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 8 Cognitive function endpoint mean scores.
Comparison 1 Antidepressant versus placebo, Outcome 9 Change in MMSE mean scores.
Comparison 1 Antidepressant versus placebo, Outcome 10 Activities of daily living, endpoint values at 6‐13 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 11 Activities of daily living at 6‐9 months.
Comparison 1 Antidepressant versus placebo, Outcome 12 Tolerability: Number of dropouts at 6‐13 weeks.
Comparison 1 Antidepressant versus placebo, Outcome 13 Tolerability: Number of dropouts at 6‐9 months.
Comparison 1 Antidepressant versus placebo, Outcome 14 Safety: number experiencing at least one adverse event.
Comparison 1 Antidepressant versus placebo, Outcome 15 Safety: N experiencing at least one event of dry mouth.
Comparison 1 Antidepressant versus placebo, Outcome 16 Safety: N experiencing at least one event of fatigue.
Comparison 1 Antidepressant versus placebo, Outcome 17 Safety: N experiencing at least one event of constipation.
Comparison 1 Antidepressant versus placebo, Outcome 18 Safety: N experiencing at least one event of dizziness.
| Antidepressant treatment compared with placebo for depression in dementia | ||||||
| Patient or population: patients with depression and dementia Settings: outpatient (except Roth 1996, which was mixed in‐ and outpatients) Intervention: antidepressant treatment Comparison: placebo treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Antidepressant | |||||
| Depression endpoint mean scores at 6 to 13 weeks | The standardised depression ratings scale endpoint mean score in the antidepressant group was 0.10 points lower (0.26 lower to 0.06 higher) | 614 | ⊕⊕⊕⊕ high | No evidence of an effect of antidepressants on depression in dementia | ||
| Number of responders (ITT) at 6 to 12 weeks | 377 per 1000 | 509 per 1000 (326 to 690) | OR 1.71 (0.80 to 3.67) | 116 | ⊕⊕⊝⊝ | No evidence of an effect of antidepressants regarding response to treatment for depression in dementia |
| Number of patients with remission (ITT) at 6 to 12 weeks | 217 per 1000 | 415 per 1000 (285 to 559) | OR 2.57 [1.44, 4.59] | 240 | ⊕⊕⊕⊝ | Evidence of a positive effect of antidepressants on remission of depression in dementia |
| Cognitive function endpoint mean scores at 6 to 12 weeks | The MMSE endpoint mean score in the antidepressant group was 0.33 points higher [1.31 lower to 1.96 higher] | (194) | ⊕⊕⊕⊝ | No evidence of an effect of antidepressants on cognitive function in patients with depression and dementia | ||
| Activities of daily living, endpoint values at 6 to 13 weeks | The standardised mean difference in ADL endpoint mean scores in the antidepressant group was 0.05 points lower [0.36 lower to 0.25 higher] | 173 | ⊕⊕⊕⊕ high | No evidence of an effect of antidepressants on ADLs in patients with depression and dementia. | ||
| Number of dropouts at 6 to 13 weeks | 179 per 1000 | 248 per 1000 (189 to 318) | OR 1.51 (1.07 to 2.14) | 836 | ⊕⊕⊕⊝ | Evidence of a negative effect of antidepressants on staying in treatment in patients with depression in dementia |
| Number of patients experiencing at least one adverse event | 384 per 1000 | 492 per 1000 (430 to 553) | OR 1.55 (1.21 to 1.98) | 1073 | ⊕⊕⊕⊝ | Evidence of a negative effect of antidepressants related to side effects in patients with depression and dementia. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). A SMD of 0.2 is often considered to represent a small effect size, 0.5 a moderate effect size and 0.8 a large effect size. | ||||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1The quality of the evidence was downgraded due to indirectness (the definitions of “response” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”) and imprecision (comparison was underpowered due to low number of total number of participants). 2The quality of the evidence was downgraded due to indirectness (the definitions of “remission” were different in the studies and some could be considered surrogate measures, e.g. “best clinical judgement”). 3The quality of the evidence was downgraded due to imprecision (relatively low number of participants and wide confidence intervals). 4 The quality of the evidence was downgraded due to imprecision (the analysis is underpowered; also, the 95% CI around the pooled or best estimate of effect include both little effect and appreciable harm). 5The quality of evidence was downgraded due to selective reporting. | ||||||
| Outcome measure | Abbreviation | Reference | Type of measure | Brief description | Used in |
| Depression rating scales | |||||
| Hamilton Depression Rating Scale | HAMD | depressive symptom levels | Clinician‐rated, multiple choice rating scale of depressive symptom severity designed to be sensitive to change with treatment in the general adult population. | ||
| Cornell Scale for Depression in Dementia | CSDD | depressive symptom levels | For the diagnosis of depression in patients with a dementia syndrome administered by a clinician. It takes 20 minutes with the carer and 10 minutes with the patient. The scale has 19 items, rated on a 3 point scale: absent, mild or intermittent and severe, based on the week prior to the interview. | ||
| Montgomery Asberg Depression Rating Scale | MADRS | depressive symptom levels | A 10‐item clinician‐rated diagnostic questionnaire to measure the severity of depressive symptomatology in mood disorders. | ||
| Geriatric Depression Scale | GDS | depressive symptom levels | A 30‐item, self‐report assessment used to identify depression in the elderly. The simple response format (yes/no questions) makes it more suitable for use in those with cognitive impairment. | ||
| Cognitive measure | |||||
| Mini‐mental State Examination | MMSE | level of cognitive functioning | A 30‐point clinician‐administered cognitive test for cognitive impairment, assessing orientation, concentration, memory, language, and visuo‐spatial function. Higher scores indicate better functioning. | All included studies | |
| Activities of daily living | |||||
| Psychogeriatric dependency rating scales ‐ ADL subscale | PGDRS‐ADL | need for assistance with functional abilities | Physical capacity consists of 7 sub‐categories. Higher scores indicate more disability. | ||
| Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living Scale | ADCS‐ADL | functional ability | Informant‐based, last 4 weeks. Higher score indicates better performance. | ||
| Functional Independence Measure | FIM | need for assistance with functional abilities | 18 items on self‐care, sphincter control, mobility, locomotion, communication, social cognition. Higher scores indicate more disability. | ||
| Older American Resources and Services | OARS‐ADL | functional ability | An 14‐item assessment for physical function, including bathing, dressing, grooming, and continence, relying on self report. Higher scores indicate better functioning. | ||
| Seoul‐Instrumental Activities of Daily Living | SIADL | instrumental everyday activities | A 15‐item instrument to assess complex functions of daily living, with a total score from 0 to 45. Higher scores reflect worse function. | ||
| Trial | dementia criteria | depression criteria | number of patients | duration | intervention | mean age | mean MMSE | mean depression rating scale score |
| NINCDS‐ADRDA for AD | three or more from Olin's criteria for depression in AD | 84 | 8 weeks | 5 mg/day of escitalopram, increased 5 mg/day every two weeks, up to a maximum dosage of 15 mg/day | 75.2 (6.9) | 18.85 | CSDD: 11.39 | |
| NINCDS‐ADRDA for probable or possible AD | depression ≥ 4 weeks's duration potentially needing antidepressants; CSDD ≥ 8 | 326 | 39 weeks | sertraline 70 mg/d (target dose: 150 mg/d), mirtazapine 24 mg/d (target dose: 45 mg/d) | 79.3 | 18.1 | CSDD: 12.9 | |
| DSM‐IV for dementia (AD, VD, and mixed) | DSM‐IV major depressive disorder and CSDD | 31 | 6 weeks | venlafaxine (37.5‐131.25 mg/d, mean = 75 mg/d) | 77.6 (6.4) | (range: 10‐24) | MADRS: 24.5 (7.1) | |
| DSM‐III‐R for PDD | DSM‐III‐R 290.21(mildly depressed) | 127 | 8 weeks | maprotiline (25 mg titrated to 75 mg/d, mean max. dose 59 mg/d) | 80 (48‐96) | 15.4 (0‐30) | GDS (median): 8 | |
| NINCDS‐ADRDA for probable AD | DSM‐VI for major depressive episode | 44 | 12 weeks | sertraline (25 mg titrated to 150 mg/d, mean peak dose 113 mg) | 77.7 | 16.9 | Ham‐D: 22.75 | |
| NINCDS‐ADRDA for probable AD | DSM‐III‐R for dysthymia or major depression | 24 | 6 weeks + 6 weeks | clomipramine (25 mg titrated to 100 mg/d) | 72 (7.2) | 21.5 (6.2) | Ham‐D:17.5 (6.0) | |
| NINCDS‐ADRDA for probable AD | DSM‐IV criteria for either major or minor depression | 41 | 6 weeks | fluoxetine (10 mg titrated to 40 mg/d) | 70.8 | 23.2 | Ham‐D: 16.5 | |
| DSM‐III for PDD | DSM‐III (major depressive disorder) | 28 | 8 weeks | imipramine (mean dose 83 mg/d) | 72 (8) | 17.5 (5.1) | Ham‐D: 18.9 (3.8) | |
| DSM‐IV for AD | Criteria for depression of AD | 131 | 12 weeks | sertraline 50 mg/d increased to 100 mg/d, mean = 93.1 mg/d) | 77.3 (8.0) | 20.0 (4.6) | CSDD (median): 13 (1st and 3rd quartile: 9, 18) | |
| DSM‐III for dementia | DSM‐III for major depressive episode | 726 | 6 weeks | moclobemide (400 mg/d) | 74.4 (8.5) | 20.2 (4.8) | 24.5 (5.3) | |
| (extension of Rosenberg 2010) | DSM‐IV for AD | Criteria for depression of AD | 131 | 24 weeks | randomised treatment with sertraline for at least partial responders after week 12 | 77.3 (8.0) | 20.0 (4.6) | CSDD (median): 13 (1st and 3rd quartile: 9, 18) |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Depression endpoint mean scores at 6‐13 weeks Show forest plot | 8 | 614 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.26, 0.06] |
| 1.1 SSRIs | 5 | 400 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.13 [‐0.33, 0.07] |
| 1.2 Mirtazapine | 1 | 134 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.02 [‐0.37, 0.33] |
| 1.3 Venlafaxine | 1 | 31 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.09 [‐0.80, 0.62] |
| 1.4 TCA | 2 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.67, 0.46] |
| 2 Cornell Scale for Depression in Dementia (CSDD) Show forest plot | 4 | Mean Difference (Random, 95% CI) | Subtotals only | |
| 2.1 At week 6‐13 | 3 | 433 | Mean Difference (Random, 95% CI) | ‐0.10 [‐0.99, 0.78] |
| 2.2 At 6‐9 months | 2 | 357 | Mean Difference (Random, 95% CI) | 0.59 [‐1.12, 2.30] |
| 3 Hamilton Depression rating Scale (HDRS) Show forest plot | 4 | 134 | Mean Difference (IV, Fixed, 95% CI) | ‐0.85 [‐2.65, 0.95] |
| 4 Number of responders (ITT) at 6‐12 weeks Show forest plot | 3 | 116 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.80, 3.67] |
| 4.1 SSRI | 2 | 85 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.42 [0.97, 6.09] |
| 4.2 venlafaxine | 1 | 31 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.17, 3.11] |
| 5 Number of responders (ITT) at 24 weeks Show forest plot | 1 | 131 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.72, 2.92] |
| 6 Number of patients with remission (ITT) at 6‐12 weeks Show forest plot | 4 | 240 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.57 [1.44, 4.59] |
| 6.1 SSRI | 3 | 216 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.22 [1.20, 4.12] |
| 6.2 TCA | 1 | 24 | Odds Ratio (M‐H, Fixed, 95% CI) | 9.0 [1.42, 57.12] |
| 7 Number of patients with remission (ITT) at 24 weeks Show forest plot | 1 | 131 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.80, 3.82] |
| 8 Cognitive function endpoint mean scores Show forest plot | 6 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 8.1 Mini‐mental state scores at 6‐12 weeks | 5 | 194 | Mean Difference (IV, Fixed, 95% CI) | 0.33 [‐1.31, 1.96] |
| 8.2 Mini‐mental state scores at 6‐9 months | 1 | 131 | Mean Difference (IV, Fixed, 95% CI) | 1.0 [‐1.14, 3.14] |
| 9 Change in MMSE mean scores Show forest plot | 6 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 9.1 at 6 to13 weeks | 5 | Mean Difference (Fixed, 95% CI) | 0.19 [‐0.81, 1.19] | |
| 9.2 at 6‐9 months | 2 | Mean Difference (Fixed, 95% CI) | ‐0.38 [‐1.90, 1.13] | |
| 10 Activities of daily living, endpoint values at 6‐13 weeks Show forest plot | 4 | 173 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.05 [‐0.36, 0.25] |
| 11 Activities of daily living at 6‐9 months Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 12 Tolerability: Number of dropouts at 6‐13 weeks Show forest plot | 9 | 836 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.51 [1.07, 2.14] |
| 12.1 SSRI | 5 | 462 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.88, 2.21] |
| 12.2 venlafaxine | 1 | 31 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.5 [0.68, 17.96] |
| 12.3 mirtazapine | 1 | 164 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.79 [0.71, 4.49] |
| 12.4 older antidepressants | 3 | 179 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.69, 2.80] |
| 13 Tolerability: Number of dropouts at 6‐9 months Show forest plot | 2 | 457 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.83, 1.88] |
| 14 Safety: number experiencing at least one adverse event Show forest plot | 3 | 1073 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.55 [1.21, 1.98] |
| 14.1 Older antidepressants | 2 | 747 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.41 [1.06, 1.89] |
| 14.2 Mirtazapine | 1 | 164 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.83 [0.93, 3.57] |
| 14.3 SSRI | 1 | 162 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.11 [1.08, 4.13] |
| 15 Safety: N experiencing at least one event of dry mouth Show forest plot | 5 | 1044 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.80 [1.23, 2.63] |
| 15.1 Older antidepressants | 3 | 874 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.71 [1.09, 2.68] |
| 15.2 SSRI | 2 | 170 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.04 [1.01, 4.12] |
| 16 Safety: N experiencing at least one event of fatigue Show forest plot | 3 | 982 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.22 [0.79, 1.87] |
| 16.1 Older antidepressants | 2 | 853 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.28 [0.78, 2.10] |
| 16.2 SSRI | 1 | 129 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.06 [0.45, 2.50] |
| 17 Safety: N experiencing at least one event of constipation Show forest plot | 5 | 1044 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.18 [0.76, 1.83] |
| 17.1 Older antidepressants | 3 | 874 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.18 [0.68, 2.06] |
| 17.2 SSRI | 2 | 170 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.17 [0.56, 2.43] |
| 18 Safety: N experiencing at least one event of dizziness Show forest plot | 5 | 1044 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.00 [1.34, 2.98] |
| 18.1 Older antidepressants | 3 | 874 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.64 [1.00, 2.68] |
| 18.2 SSRI | 2 | 170 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.93 [1.48, 5.80] |
