What is the therapeutic value of antidepressants in dementia? A narrative review

Objectives: Antidepressants are commonly used in dementia. Depression is a frequent and important co-morbidity in dementia and antidepressants are often used to treat depression and more widely. However there are questions about their utility in depression in dementia and other behavioural and psychological symptoms of dementia (BPSD). The aim of this narrative review is to summarise the evidence on whether there is therapeutic value in prescribing antidepressants to people with dementia. Methods: A PubMed search was performed to identify RCTs that prescribed antidepressants to people with dementia, either in the treatment of BPSD (depression, anxiety, agitation/aggression, psychosis, apathy) or for secondary outcomes (quality of life, carer burden, activities of daily living, cognition, clinical severity, adverse events). Results: Thirty-six RCTs were identified (participant n=3,386). A consistent finding in well-designed blinded placebo controlled trials in dementia is the lack of positive effect of antidepressants on outcomes of interest including depression. One large well-designed study has reported a significant reduction in agitation in people with dementia, but at the expense of clinically significant adverse events. Otherwise change observed in open trials is also seen in the placebo group, suggesting any effect is not attributable to the prescription of antidepressants. Conclusions: It is striking how few data there are on indications other than depression. We should question the use of antidepressants in dementia. Definitive trials of clinical effectiveness of specific indications such as anxiety and agitation in dementia and discontinuation of antidepressants in dementia are needed

The effect of treatment with Selective Serotonin Reuptake Inhibitors incomparison to placebo in the progression of dementia: a systematic review and meta-analysis

Background: selective serotonin reuptake inhibitors (SSRIs) may affect the neurodegenerative process of dementia, enhancing cognition. This systematic review aims to determine whether SSRIs influence cognitive performance, mood and function in people with any type of dementia.Method: randomised placebo-controlled studies of SSRIs in people with dementia, which recorded cognitive outcomes, were identified in ALOIS (ALzheimer's and cOgnitive Improvement Studies register) in April 2013 and updated in January 2015. Data were extracted on cognition, agitation, mood, activities of daily living (ADLs) and adverse events. End of treatment statistics were calculated.Results: twelve studies met inclusion criteria (1,174 participants), of which seven studies (710 participants) provided data for meta-analysis on cognition. There was no difference in MMSE score at end of treatment; mean difference (MD) was 0.28 (95% CI −0.83 to 1.39) (six studies, 470 participants). For change in MMSE scores, there was a small improvement; MD was 0.53 (95%CI −0.07 to 1.14) (three studies, 352 participants). The remaining studies showed no improvement in cognition. There was no statistically significant benefit of SSRIs on mood (four studies, 317 participants); standard mean difference (SMD) −0.10 (95% CI −0.39 to 0.2), agitation (three studies, 189 participants); SMD −0.01(95% CI −0.86 to 0.83), or ADLs at end of treatment (four studies, 336 participants); SMD −0.15(95% CI −0.45 to 0.15). There was no difference in mortality between the two groups. Study quality was mixed with concerns over incomplete data.Conclusion: a small number of relatively low-powered studies showed no benefit or harm from SSRIs in terms of cognition, mood, agitation or ADLs. Large, methodologically robust studies are needed

Efficacy of antidepressants for depression in Alzheimer's disease: systematic review and meta-analysis

Background: Depression is common in people with Alzheimer’s disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting. Objectives: To systematically review evidence on efficacy of antidepressant treatments for depression in AD. Methods: Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed. Results: Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97–3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD –0.13; 95% CI –0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials. Conclusion: Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

Abstract Background Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD. Methods We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. Results Amyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. Conclusions Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology