Efficacy of milnacipran on the depressive state in patients with Alzheimer's disease

doi:10.1016/j.pnpbp.2006.03.004

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 30, Issue 7, 30 September 2006, Pages 1342-1346

https://doi.org/10.1016/j.pnpbp.2006.03.004 Get rights and content

Abstract

An open-labeled study was conducted to examine the efficacy of selective serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran in treating depression in Alzheimer's disease (AD) patients. Eleven patients with AD showing major depressive symptoms were examined. Ten of 11 patients demonstrated an over 50% decrease in their HAM-D scores from the baseline, and 8 of 11 patients reached remission (HAM-D score ≦ 7) within 12 weeks of the start of milnacipran treatment, and their GAF score was also remarkably improved. Although in 11 patients, two patients showed a mild hypomanic state and one patient showed daytime somnolence, these problems were quickly solved after a decrease in the daily dose or discontinuation of milnacipran. In addition, the treatment had no negative effects on cognitive function of the patients. Our study results suggest that milnacipran is a promising medicine for depressive state in AD patients.

Introduction

In Alzheimer's disease (AD) patients, depression is not a rare condition. The prevalence of major depression has been reported to be within the range of 20–25% (Migliorelli et al., 1994, Olin et al., 2002) of AD patients. Depression in AD patients is associated with earlier placement out of the community into a nursing home (Steele et al., 1990), and is also associated with greater impairments in the quality of life (Gonzales-Salvdor et al., 2000) as well as with increased caregiver depression and burden (Gonzales-Salvdor et al., 1999). Although some tricyclic anti-depressants (TCAs) have been found to improve depression in AD, the anti-cholinergic effects of these medicines are critical to cognitive function in AD patients (Teri et al., 1991). Recently, serotonin selective reuptake inhibitors (SSRIs) have been recommended for depression in AD patients due to their minimal anti-cholinergic effects, although their efficacy has remained controversial and further studies are needed.

Milnacipran (1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane hydrochloride) is a novel anti-depressant agent that is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) (Puech et al., 1997, Briley, 1998), and is reported to be devoid of any postsynaptic activity (Moret et al., 1985). Although milnacipran has been reported to be effective and safe for elderly depressive patients (Tignol et al., 1988), thus far there has been no study focusing on its effects on depression in AD patients. We describe here the efficacy and safety of milnacipran on depression with AD through its open trial for 11 patients. To our knowledge, this is the first paper reporting SNRI treatment of depression in AD patients.

Section snippets

Patients

A consecutive series of 11 patients were enrolled in this study, and all 11 participants were recruited from the outpatient clinic of Ishizaki Hospital, and provided written informed consent for study participation. The study was carried out in accordance with the ethics and principles embodied in the Declaration of Helsinki of 1975. Clinical diagnosis of AD was made utilizing DSM-IV (American Psychiatric Association, 1994) and NINCDS/ADRDA (McKhann et al., 1984) criteria. In addition, all 11

Results

Eight patients took milnacipran for more than 12 weeks (72.7%); and 3 patients discontinued the treatment within 12 weeks. The reasons for discontinuation were emergence of hypomanic state for one patient (Case 5) and dropout for two patients (Cases 9 and 10). Case 10, however, resumed the treatment of milnacipran due to recurrence of depression thereafter.

Table 1 shows the background characteristics of the 11 patients analyzed. Their mean age was 75.2 ± 9.4 (range 56–84) years. Of the 11

Discussion

In our study, all the 11 patients demonstrated a remarkable improvement in depression with milnacipran treatment. Within 12 weeks, 8 of 11 patients reached remission (remission rate, more than 70%). Previous studies on depressive state in AD patients treated with anti-depressants demonstrated that the remission rates using clomipramine and fluoxetine, respectively, are 82% (Petracca et al., 1996) and 47% (Petracca et al., 2001), and that the rate of 30% reduction in HAM-D scores using

Acknowledgment

This study was supported by a Research Grant for Longevity Sciences (14C-4) from the Ministry of Health, Labor and Welfare of Japan.

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La dépression et les symptômes comportementaux et psychologiques de la démence (SCPD) ont un impact important sur l’évolution de la maladie démentielle car ils favorisent l’accélération du déclin cognitif et influencent le pronostic fonctionnel et vital. Le prescripteur doit être particulièrement prudent dans le maniement des antidépresseurs chez le sujet âgé car la plupart des études ont certes inclus des patients âgés d’au moins 65 ans, mais rarement de plus de 75 ans ; ces patients étant en outre sélectionnés sur l’absence de tout critère de fragilité. Ainsi, les inhibiteurs de la recapture sélectifs de la sérotonine (IRSS), qui semblaient initialement ne comporter que peu de risques, ont été associés, au fur et à mesure de leur utilisation en pratique clinique courante, à des effets secondaires nombreux et dangereux tout particulièrement chez les sujets âgés. Nous manquons à l’heure actuelle de données suffisantes pour évaluer la balance bénéfice–risque des antidépresseurs dans le traitement de la dépression et des SCPD chez les patients atteints de la maladie d’Alzheimer ou d’autres affections démentielles. Très peu de molécules ont été testées par des essais thérapeutiques dans ces indications. Malgré leurs limites, les études sur le citalopram et le moclobémide ont montré des effets probables avec des risques faibles d’effets indésirables, que ce soit sur les signes dépressifs ou sur les SCPD. Il est nécessaire d’évaluer l’efficacité et les effets secondaires des antidépresseurs chez le sujet âgé dément à travers un grand nombre d’études.
Depression and behavioural and psychological symptoms of dementia (BPSD) have a significant impact on the worsening of dementia because they increase the cognitive and functional decline and they have a significant impact on the vital prognosis. Physicians should be particularly careful in the use of antidepressants in the elderly, particularly in the frail elderly. Indeed, most studies have included patients aged at least 65 years without frailty criteria, but rarely those aged over 75 years and/or frail. As they are used in clinical practice, selective serotonin reuptake inhibitors, which initially appeared to have low risks, have been associated with many and dangerous adverse effects, particularly in elderly subjects. At present, there is a lack of data to assess the benefit–risk ratio of antidepressants in the treatment of depression and BPSD in patients with Alzheimer's disease or other dementias. Among the drugs frequently used in studies in order to evaluate these indications, citalopram and moclobemide are those associated with a low risk of adverse events and a significant effectiveness on depression signs and behavioural and BPSD. It is necessary to assess the effectiveness and adverse effects of antidepressants in demented elderly subjects through several studies.
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To clarify the profile of depressive symptoms in major depressive episodes in patients with Alzheimer's disease (AD-MD), we compared AD-MD with major depressive disorder in non-demented elderly patients (MDD) matched for age, using the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇). In addition, to clarify which depressive symptoms of AD patients respond to treatment with the selective serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran, we compared the HAM-D₁₇ average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score, and GAF score according to the DSM-IV evaluation of AD-MD patients at baseline and at the endpoint (12 weeks).
Depressive mood, loss of interest in hobbies and social activities and anxiety (psychic) scored the highest in both AD-MD and MDD groups, while psychomotor retardation scored significantly higher in AD-MD, and insomnia and anxiety (somatic) significantly did so in MDD. We also found that depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, and hypochondriasis remarkably improved in patients of AD-MD treated with milnacipran.
Our results suggest that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising to treat a broad range of depressive symptoms in AD-MD patients.
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Case reportEfficacy of milnacipran on the depressive state in patients with Alzheimer's disease

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgment

Geriatr Psychiatry

Neuropharmacology

Am J Geriatr Psychiatry

Psychosomatics

Diagnostic and statistical manual of mental disorders

Specific serotonin and noradrenaline reuptake inhibitors (SNRIs). A review of their pharmacology, clinical efficacy and tolerability

Hum Psychopharmacol

“Mini-mental state”: a practical method for grading the mental state of patients for the clinician

J Psychiatr Res

The stress and psychological morbidity of the Alzheimer patient caregiver

Int J Geriatr Psychiatry

Quality of life of patients with dementia in long-term care