The Efficacy of Sertraline,Escitalopram,and Nicergoline in the Treatment of Depression and Apathy in Alzheimer’s Disease: The Okayama Depression and Apathy Project (ODAP)

INTRODUCTION

Alzheimer’s disease (AD) is the most common cause of dementia, with primary cognitive symptoms including recent memory impairments, disorientation, and recall disorder [1]. Additionally, 50% and 65% of patients with AD exhibit affective symptoms such as depression and apathy, respectively [2, 3]. The symptoms of major depressive disorder that manifest in patients with AD include dysphoria, anxiety, loss of interest, and sleep disturbances [1]. Depression and poor mental well being are associated with a decreased quality of life (QOL) in patients with AD [4]. Apathy is conceptualized as motivational impairment and is also considered to considerably reduce QOL [4]. Therefore, effective treatment for depression and apathy in these patients is of great importance. In the present study we evaluated the efficacy of two anti depressants, sertraline and escitalopram, and nicergoline, an antipathy drug, for the treatment of depression and apathy in patients with AD.

MATERIALS AND METHODS

The present studywas a randomized, single-blind, multi-center, prospective, observational study, conducted from April 2017 to December 2018. Dementia of AD type was diagnosed by neurologists as probable or possible AD using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association [5]. In the present study, 33 patients with AD were enrolled at the Okayama University Hospital or one of its affiliated hospitals and treated with a stable dose of anti-dementia drugs. All selected patients showed a high Geriatric Depression Scale (GDS)score of >5 or a high Apathy Scale (AS) score of >16 [6, 7]. After the initial assessment of cognitive and affective functions, participants were randomly assigned to one of three drug groups to target the symptoms of depression and apathy (escitalopram, n = 13; sertraline, n = 11; nicergoline, n = 9) and a 3-month (M) treatment course was initiated. The dosage of each drug was decided according to each patient’s physical condition (i.e., body weight, drug sensitivity) and prescribed within the optimal dose range. Patients were evaluated using the Mini-Mental State Examination (MMSE) and the Hasegawa Dementia Rating Scale-Revised (HDS-R) to assess cognitive function, the GDS and AS to assess affective function [8, 9]. These assessments were performed at baseline and following 3 M of treatment by professional medical staff blinded to the drug treatment information. At baseline period, we confirmed Fazekas periventricular hyper intensity (PVH)/deep and subcortical white matter hyper intensity (DSWMH) scores [10, 11] in nicergoline group to assess ischemic change in brain MRI imaging.

All participants provided written informed consent and the Ethical Committee of Okayama University approved the present study. We also obtained exempted approval from the institutional review board based on our guidelines since we used an anonymized and untraceable dataset (approval no.K1612-022).

Statistical analyses were performed using SPSS (version 22.0.0.0; IBM, Armonk, NY, USA). Comparisons between baseline characteristics (gender and age) and baseline MMSE, HDS-R, GDS, and AS scores were conducted using the Kruskal–Wallis test for continuous variables and Pearson’s chi-squared test (χ²) for comparison of proportions. The Wilcoxon rank sum test was used to analyze the mean score change in cognitive (MMSE, HDS-R) and affective (GDS, AS) functions between baseline and 3 M after initiating treatment.

RESULTS

The clinical characteristics of the three drug groups including age, gender, average drug dose, and the scores of cognitive (MMSE and HDS-R) and affective (GDS and AS) function tests are shown in Table 1. The average Fazekas PVH and DSWMH scores in the nicergoline group were 2.0±1.3 and 2.2±0.9, respectively.

The mean age of the sertraline group (73.0±7.3 years old) was younger than the escitalopram (79.1±6.1 years old) and nicergoline (80.1±5.4 years old) groups (^*p = 0.03 and ^#p = 0.04, respectively). The subjects in the three drug groups showed a mild decrease in MMSE (sertraline, 21.5±4.9; escitalopram, 24.2±5.5; nicergoline, 21.4±4.4) and HDS-R (sertraline, 19.5±5.3; escitalopram, 21.2±4.9; nicergoline 18.2±4.9) scores, and a mild elevation in GDS (sertraline, 7.3±2.4; escitalopram, 8.2±3.5; nicergoline, 5.1±5.2) and AS (sertraline, 20.8±5.2; escitalopram, 20.3±8.2; nicergoline, 16.9±7.7)scores from baseline to 3 M. No significant differences were found in the scores of the cognitive (MMSE and HDS-R) and affective (GDS and AS) functiontests, or in thegender of patients between the three drug groups.

The changes in the MMSE and HDS-R scores from baseline to 3 M after treatment were not significant among the three groups (Table 1). The mean changes in the affective function test scores are shown in Fig. 1. The escitalopram group showed significant improvements in the GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, ^*p = 0.04), but the sertraline and nicergoline groups did not show any improvements in this score (Table 1, Fig. 1). Alternatively, the sertraline group showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, ^*p = 0.05). The escitalopram group showed a small improvement in AS score, but the nicergoline group showed a decline in this score (Table 1, Fig. 1).

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Fig.1

The mean score change in affective function (GDS and AS) in patients with AD from baseline to 3 M after treatment with sertraline, escitalopram, and nicergoline. Note the significant improvement in GDS score from baseline to 3 M in the escitalopram group (^*p = 0.04), and inAS score in the sertraline group (^*p = 0.05). GDS, Geriatric Depression Scale; M, months; AD, Alzheimer’s disease; AS, Apathy Scale.

DISCUSSION

In the present study, we evaluated the efficacy of three drugs, sertraline, escitalopram, and nicergoline, in the treatment of depression and apathy in patients with AD. A 3 M period of sertraline treatment significantly improved apathy, while escitalopram treatment over this period significantly improved depression. Nicergoline had no positive impact on either symptom (Table 1, Fig. 1).

Neuropsychiatric symptoms of dementia, such as depression and apathy, are associated with a decreased QOL in AD patients. Previous studies have shown that depression and apathy occur in 50% and 65% of patients with AD, respectively [2, 3]. Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and escitalopram are commonly used in the treatment of depression in patients with AD. SSRIs increase extracellular serotonin, dopamine, and noradrenaline levels in the amygdala and nucleus accumbens [12, 13]. A previous study reported that sertraline treatment improved mild to moderate depression in patients with AD, but another study reported no improvements[2, 14]. Sertraline is a naphthalenamine derivative with the predominant pharmacological action of inhibiting presynaptic reuptake of serotonin from the synaptic cleft [15]. One case report showed the efficacy of sertraline (100 mg/day)for apathy in patients with Neuro-Behcet’s disease[16], while another study showed the efficacy of escitalopram (15 mg/day) for agitated patients with AD [17]. However, the present study is the first to investigate the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.

Manufacturers describe the recommended doses of escitalopram, sertraline, and nicergoline to be 10–20 mg, 25–100 mg, and 15 mg/day, respectively. In the present study, the dosage of each drug was decided according to each patient’s physical condition (i.e., body weight, drug sensitivity) within the optimal dose range. The average doses prescribed used in the current study for escitalopram, sertraline, and nicergoline were 7.3 mg, 31.8 mg, and 14.5 mg, respectively (Table 1). Small dosages of sertraline and escitalopram showed efficacy for the treatment of apathy and depression, respectively, in patients with AD (Table 1, Fig. 1). One limitation of this study was the limited study size. If a larger sample size was used, more significant benefits may have been observed.

In conclusion, this study showed the efficacy of sertraline and escitalopram for apathy and depression, respectively, in patients with AD patients. On the other hand, nicergoline showed no significant efficacy for depression and apathy in AD patients.