Selective Serotonin Reuptake Inhibitors for Mild Cognitive Impairment : A Systematic Review

Background and purpose: Mild cognitive impairment (MCI) can be the first sign of impending dementia, particularly Alzheimer’s disease (AD). Selective serotonin reuptake inhibitors (SSRIs) could potentially impact on the neurodegenerative process of MCI and enhance memory and cognition by promoting neurogenesis in the hippocampus. The aim of this study was to systematically review randomised, placebocontrolled trials of SSRIs in patients with MCI. Methods: The authors systematically reviewed literature on the efficacy and safety of treatment of MCI with SSRIs to determine if treatment with SSRIs reduced the rate of cognitive decline in such patients, compared with a placebo intervention. MEDLINE (from 1948 to March 2013), and EMBASE (from 1980 to March 2013), were searched in March 2013 for publications relating to SSRIs and MCI. One author screened titles and abstracts and obtained full texts of potentially eligible studies. Full papers were scrutinised independently by both authors to determine whether they fulfilled the inclusion criteria. Results: Of 4480 abstracts screened, 48 full texts were retrieved for scrutinisation. Of these, one study met the inclusion criteria. It comprised 58 participants with MCI , who were randomised to either fluoxetine 10mg/day, increased to 20mg/day after 1-2 weeks for a duration of 8 weeks, or placebo and were followed up for the duration of the treatment but not after treatment had ended. Cognition was significantly better in the fluoxetine group compared to placebo at the end of treatment. There was a high drop-out rate, particularly in the treatment group. Conclusions: The study identified showed that patients allocated fluoxetine had better cognition at the end of treatment compared to the placebo group. However, the sample size was small and further randomised clinical trials are needed to confirm whether fluoxetine in MCI reduces the rate of cognitive decline and whether any beneficial effects are sustained after treatment ends. INTRODUCTION Description of the condition Mild cognitive impairment (MCI) may be the first sign of impending dementia, particularly Alzheimer’s disease (AD). It can be diagnosed according to the Petersen Criteria [1]. The rate of progression to dementia varies considerably between individuals, with some patients never advancing to established dementia. Treatment in the early stages of MCI may delay progression to dementia. Dementia is a clinical syndrome that is characterised by an acquired, progressive decline in cognition that occurs over a period of months to years. It affects approximately 5% of those aged over 60 rising to about 30% of those over 85 [2]. As the proportion of older people in the population increases, it is estimated that the prevalence of dementia in the UK will double in the next 30 years [3]. Description of the intervention Selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective in the treatment of depression [4]. This Central Dixon and Mead (2013) Email: 0919147@sms.ed.ac.uk J Neurol Disord Stroke 1(3): 1022 (2013) 2/7 class of drugs includes fluoxetine, sertraline, paroxetine, citalopram and fluvoxamine. SSRIs are highly selective for the neurotransmitter 5-hydroxytryptamine receptor (5HT; serotonin receptor). Depression is thought to be associated with a functional deficit in 5HT. SSRIs act to improve mood in depression by increasing the extracellular levels of the 5HT by inhibiting its reuptake into the presynaptic cell. Over the years the therapeutic uses of have become more diverse, being used successfully to treat other conditions such as obsessive–compulsive disorder [5], panic disorder [6] and bulimia [7]. There has also been recent evidence regarding their potential in stroke recovery. Plausible mechanisms of action (other than enhancing mood), include neurogenesis, neuroprotective effects and indirect effects on the adrenergic system, through upregulation of beta 1 receptors [8]. How SSRIs might reduce the rate of cognitive decline in people with MCI Current treatment of dementia targets the cholinergic system. However, there is evidence to suggest that other neurotransmitters contribute to age-related cognitive decline in addition to cholinergic dysfunction [9,10,11]. Other neurotransmitters, including serotonin interact with the cholinergic system, thereby playing a role in cognitive processes [12]. Furthermore, it has been reported that the degree of cholinergic activation required in keeping the brain active could be reduced by a concurrent activation of the central serotonergic transmission [13]. SSRIs could have a potential impact on the neurodegenerative process of MCI and help to enhance memory and cognition by promoting neurogenesis, since they have a neurotrophic effect and neurotrophins are vital for nerve regeneration. Increased neurotrophin expression in the hippocampus has been demonstrated with SSRIs [14]. Animal studies have demonstrated that SSRIs promote dendritic branching and neurogenesis in adult rats [15,16]. Migration of new neurones to damaged areas of brain has been found to occur with SSRIs [17] in addition to neurogenesis within damaged areas [18]. Indeed, in Alzheimer’s dementia, reduced levels of serotonin and its precursors such as tryptophan have been convincingly demonstrated [19]. SSRIs also have a neuroprotective effect, through repressing microglial activation, thereby decreasing inflammation [20], as well as enhancing the expression of specific proteins such as hypoxia inducible factor 1 alpha [21]. SSRIs have an indirect effect on the adrenergic system, through up-regulating beta-1 receptors [22]. Cortisol dysregulation has been associated with cognitive decline [23,24,25]. Treatment with SSRIs leads to decreased cortisol secretion, which has been associated with improvement in some cognitive domains [26,27]. Several studies have demonstrated improvement in cognitive function in patients with AD treated with SSRIs [28,29]. However, the role of these agents in the treatment of MCI is currently unclear, and worthy of investigation if they can prevent loss of independence and cognitive decline in such patients. There is no systematic review, to our knowledge, of SSRIs for MCI. Aims To determine whether, in patients with MCI, treatment with an SSRI is associated with better cognition at the end of treatment than those allocated to a placebo, and whether there is evidence of other benefits such as improvement in mood and whether there is an excess of adverse events. A systematic review is the least biased method of combining data from different studies as it uses explicit systematic methods. Systematic reviews and meta-analyses are better than individual studies in informing clinical practice as they combine the information from relevant studies and can give more precise estimates of the effects of health care. Meta-analyses have the advantages of an increase in power, precision, the ability to answer questions not posed by individual studies, and the opportunity to settle controversies arising from conflicting claims. The results must be interpreted critically, however, bearing in mind any within-study biases, variation across studies and reporting biases [30]. Study question We performed a systematic review of the literature to determine the effect of an SSRI compared to placebo on cognition in patients with MCI, whether an SSRI influences disability and dependency or improves mood, and whether treatment with an SSRI is associated with an excess of side effects including morbidity and mortality. MATERIALS AND METHODS Criteria for considering studies for this review We included placebo-controlled, double-blinded, randomised studies involving SSRIs, published as abstracts only or full texts. Types of participants Trials had to recruit individuals with MCI as defined by each study, but in accordance with the generally accepted criteria of a subjective memory complaint with relatively preserved daily functioning. Studies including patients with delirium or established dementia were excluded. We included studies that used SSRI in MCI, irrespective of what the primary aim of the study was. Types of interventions Any trial that used a drug classified as SSRI such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, irrespective of treatment duration, route of administration or dose was included. Only trials that compare SSRI to placebo were included. Those that used other antidepressants or used comparisons with other alternative active treatment were excluded. Outcomes We were interested in outcomes at the end of treatment, and at the end of any follow-up. The primary outcome was cognitive performance that had been formally accessed by recognised scoring systems including, but not limited to Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) [31], MiniMental State Examination (MMSE) [32] and Clinical Dementia Rating sum of the boxes (CDR) [33]. Secondary efficacy outcomes are agitation and psychosis, mood as measured on various dementia scales, patient’s ability to perform activities of daily living, adverse events, care giver’s Central Dixon and Mead (2013) Email: 0919147@sms.ed.ac.uk J Neurol Disord Stroke 1(3): 1022 (2013) 3/7 distress, dropping out of the study for any reason (including death). Search Methods for Identification of Studies The authors systematically reviewed the literature on the efficacy and safety of treatment of MCI with SSRIs. Electronic Searches: The following electronic bibliographic databases were searched: • MEDLINE (from 1948 to March 2013), searched March 2013 • EMBASE (from 1980 to March 2013), searched March 2013 The MEDLINE search strategy was developed and adapted for the EMBASE database. In addition, the online database, Current Controlled Trials (www.controlled-trials.com) was searched (April 2013) Searching other resources: In an effort to identify further published, unpublished