Original Paper 131

Authors

N. Mokhber1, E. Abdollahian1, A. Soltanifar1, R. Samadi1, A. Saghebi1, M. B. Haghighi2, A. Azarpazhooh3

Affiliations

1

Psychiatry and Behavioral Sciences Research Center, lbn-e-Sina Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2 General Practice, Mashhad, Iran 3 Faculty of Dentistry, Institute of Health Policy, Management and Evaluation of Faculty of Medicine, University of Toronto, Toronto, Canada

Key words ▶ Alzheimer’s disease (AD) ● ▶ antidepressants ● ▶ dementia ● ▶ cognition ● ▶ depression ●

Abstract

received revised accepted

31.08.2013 01.05.2014 08.05.2014

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1377041 Published online ahead of print: 23 June 2014 Pharmacopsychiatry 2014; 47: 131–140 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence R. Samadi Psychiatry and Behavioral Sciences Research Center Ibn-e-Sina Hospital Mashhad University of Medical Sciences Mashhad 9195983134 Islamic Republic of Iran Tel.: + 98/511/711 2540 Fax: + 98/511/712 4184 [email protected]

▼

Rationale: The effects of antidepressants on mood, cognition and the daily activities of Alzheimer patients are ambiguous. The effects of antidepressants SSRIs (serotonin specific reuptake inhibitors), TCAs (tricyclic antidepressants) and SNRIs (serotonin-norepinephrine reuptake inhibitors), in particular, are unknown. Objectives: This study aimed to compare the effects of sertraline, venlafaxine and desipramine on depression, cognition and the daily activities of Alzheimer patients. Methods: This randomized double-blind trial was approved by the Research and Ethics Committees of Mashhad University of Medical Sciences. 59 moderate Alzheimer patients with major depressive disorder were randomly divided into 3 groups (sertraline, venlafaxine and

Introduction

▼

Alzheimer’s disease (AD) is a common disorder in elderly patients [1] and its prevalence is on the increase due to the growth of the elderly population [2]. In addition to cognitive deficits that are the core symptoms, co-morbidity with other psychiatric illnesses such as mood and behavioral disorders has negative effects on the course and prognosis of AD. This fact means that specific attention must be paid to treating such patients [3–6]. One of the common psychiatric disorders, which is co-morbid with AD, is depression [7]. In some studies the prevalence of depression in AD is estimated to be 15–63 % [8–10]. This co-morbidity has many adverse effects [11–13] and also adds to the burden of the caregivers of patients with AD [8, 9, 14]. Depression in AD patients may result in suicide [15], increased rates of morbidity [16] and mortality [17], loss of function in daily activities [17], somatic complaints [18],

desipramine), treated for 12 weeks (150 mg maximum dose) and assessed by the Hamilton Depression Test (HRSD), the Mini Mental State Examination (MMSE) and the Barthel index at the week 0 and the 2nd, 4th, 8th, 12th weeks thereafter. Data were analyzed by SPSS software, using ANOVA and paired t-tests. Results: In the sertraline group, the results of all 3 tests, HRSD, MMSE and Barthel, in the 12th week showed significant improvements in comparison to the baseline (P < 0.05 in all 3 tests). In the venlafaxine group, the results of MMSE and Barthel revealed significant improvements (P < 0.05 in both tests). In the desipramine group, there was a significant improvement only in the Barthel test at the 12th week (P < 0.05). Conclusion: In this trial, sertraline treatment was associated with superior effectiveness in relation to depressive, cognitive, and behavioral symptoms.

worsening of cognitive status [19], and longer stays in nursing homes [17]. The treatment of depression can reduce these problems and improve the quality of life in these patients [20, 21]. Decreased central levels of serotonin and norepinephrine are the probable causes of depression in AD [8]. Tricyclic antidepressants (TCAs) that inhibit reuptake of serotonin and norepinephrine, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most appropriate medications for this condition. SSRIs such as sertraline are one of the common treatments for depression in patients with AD [9]. The positive effects of sertraline on mood in AD have been reported in some studies [9, 17, 22, 23]. Some researchers have shown that SSRIs have more efficacy and fewer side effects than other antidepressants in individuals with AD [24]. Sertraline, citalopram and clomipramine have been more effective than placebos in patients with dementia [25]. Review articles

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Comparison of Sertraline, Venlafaxine and Desipramine Effects on Depression, Cognition and the Daily Living Activities in Alzheimer Patients

132 Original Paper

venlafaxine and desipramine on depression, cognition and the activities of daily living in Alzheimer patients.

Materials and Methods

▼

This study is a randomized double-blind clinical trial and was approved by the Research Council and Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran, in 2011–2012. The study population was outpatients who were referred to the clinics of Ebn-e-Sina and Gha’em university hospitals and who were diagnosed with mild to moderate Alzheimer dementia. The scores of 20–24 and 10–20 in the Mini Mental State Examination [MMSE] were considered as mild and moderate dementia, respectively [44]. The major depressive disorder was diagnosed according to DSM-IV and a semi-structured interview by the study psychiatrist. Neuro-imaging supported the diagnosis of Alzheimer dementia in all patients. Patients were enrolled in the study if they met the inclusion criteria (lack of contraindications for using our medications, not being on other drugs except for H2 blockers, anti-hypertensives, cardiovascular medications, and cholesterol-lowering drugs). The exclusion criteria were: use of any psychotropic drug (except for acetylcholinesterase inhibitors; as all patients were maintained on donepezil 5–10 mg/day) during the 2 weeks before referral, any other co-morbid psychiatric disorder (except for major depressive disorder), and a history of substance abuse before or during the study. After providing the necessary information for patients and their caregivers and taking their informed consent, they were enrolled in the study. Besides collecting the demographic information, at the beginning of the study, Hamilton Rating Scale for Depression (HRSD), Mini Mental State Examination (MMSE) and Barthel Index of Activities of Daily Living were done to assess mood, cognition and function of activities of daily living, respectively. The patients were randomly assigned to 3 groups: desipramine, sertraline and venlafaxine. According to guidelines, a low starting dosage of SSRI, SNRI and TCA with more gradual increases in dosage in elderly patients was considered to prevent or minimize the side effects [32]. The final dosage did not differ from those prescribed to young or middle-aged adults. The patients were initially started on 25 mg of sertraline or desipramine, or 37.5 mg of venlafaxine at night. They did not know which drug they were taking (to perform the double blinding, the drugs were encapsulated). The next week, these amounts were increased to 50 mg per day, while maintaining the same nightly dose. In order to limit the undesirable side effects, the initial dosage, when needed, was gradually increased up to 150 mg by the end of the 4th week. Sertraline was prescribed as a single dose, venlafaxine as 2 times per day, and desipramine as 3 times per day. The initial medication, however, started 4 times a day. The additional doses were placebos but presented in the identical form of the real drug. All medications were prescribed 3 times per day. The additional doses were placebos in 2 other groups whose prescribed medication was 1 or 2 doses per day. Therefore, all groups were given medication at the same time but some doses were placebos and were encapsulated in the same shape. The patients did not know which drug they were taking. Clinical follow-up, physical examination for possible side effects and retests of HRSD and MMSE were performed at the clinic at weeks 2, 4, 8, and 12, the retest of the BI was done at weeks 4 and 12. In each session, emotional support and clinical instructions

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have revealed that patients who received sertraline had better compliance compared to other SSRIs [26]. SSRIs have a better profile of side effects than other antidepressants. Some clinicians, however, are concerned about their use when depression is severe [24]. SSRIs often have to be prescribed with sedative drugs, a combination that may have negative effects on the cognitive function and quality of life in patients with AD [27]. Some authors have suggested that TCAs can be used in depression in the context of dementia [28], but their adverse effects such as anti-cholinergic side effects can increase the cognitive impairment [29]. Desipramine and nortriptyline are still used because they have fewer anti-cholinergic properties [30]. Although desipramine has the least anti-cholinergic properties of all the TCAs, it is still not an appropriate option when compared to sertraline [26]. However, a study in 2012 revealed that desipramine has neuro-protective and anti-apoptotic properties, and its effect on the neuro-degeneration process can make it a prime candidate in the treatment of AD-related depression [31]. To adjust the therapeutic dose of desipramine, clinicians should take factors such as medical health, age and concurrent medications into consideration. The usual adult dosage range of desipramine is 150–300 mg/day [32]. Although SSRIs have fewer side effects and are safer than TCAs in the elderly population [25], insomnia, irritability and gastrointestinal problems are the common side effects that may limit their use [26, 33]. Aging is associated with a decrease in sertraline clearance. In the elderly patients treated with 100 mg/day sertraline, the clearance was 40 % lower than that in younger subjects [32]. In several studies, the target dosage of sertraline has been 150 mg/day [34]. Some studies, however, have questioned the efficacy of SSRIs such as sertraline in patients with AD [35, 36]. Venlafaxine has been suggested in AD-associated depression [37], although its adverse effects may limit its use [38]. In ambulatory clinical trials of venlafaxine, using a flexible dose, the modal dose is 150 mg/day [32]. The American Psychiatric Association has suggested SSRIs as the first choice of medication in patients with dementia and depression and has recommended using other antidepressants such as venlafaxine if higher doses of SSRIs cannot be tolerated [39]. The STAR-D study has also recommended SSRIs as the best medication for depression in elderly patients and has suggested other drugs for augmenting them if an adequate response is not seen [40]. Some researchers believe that antidepressant treatments may improve the cognitive function of patients with AD [41]. It should be noted that these authors conducted their research on patients whose symptoms did not meet the full criteria for major depressive disorder and were in the first stages of dementia. It is probable that chronic and mild symptoms of depression can affect the assessment of cognitive status. On the other hand, the results of a 24-week study in 2012 showed that when compared to placebos, sertraline did not have a positive effect on the cognitive function of patients with dementia and depression [42]. Nevertheless, other studies have shown that treatment with antidepressants may improve other symptoms of AD such as daily function and general behavior [43]. In spite of the high incidence of depression in AD, there are contradictory results especially about the efficacy of antidepressants on the cognitive function of patients with dementia. Therefore, this randomized double-blind clinical trial was designed and conducted to compare the efficacy of sertraline,

Original Paper 133

Scale

Interpretation of Scores 1

MMSE

HRSD2 Barthel ADL Index (BI)

Normal to questionably significant Mild dem* Moderate dem 25–30 20–25 10–20 Normal Mild dep** Moderate dep 0–16 17–24 25–30 Total possible scores from 0–20. Lower scores indicate increased disability

1

MMSE = Mini Mental State Examination

2

HRSD: Hamilton Rating Scale for Depression

Severe dem 0–10 Severe dep 31 ≤

Table 1 Inventories used in this study.

*Dem = dementia

were provided for the patients and their families, and they were called every week in order to check for possible side effects and to encourage staying in the program. The results of these 3 groups were analyzed by SPSS software, using ANOVA, paired T-test, Tukey, and Kruskal-Wallis tests.

Mini Mental State Examination (MMSE) MMSE is a 30-point screening test, consisting of 11 items, that evaluates areas such as orientation, information recording, attention and calculation, remembering and language, all of which deteriorate in dementia. MMSE is the most commonly used current screening tool for cognitive disorders all over the world. This test is implemented by the examiner. Its cut-point is 24. Scores of 20–24, 10–20 and less than 10 represent mild, moderate and severe dementia, respectively. The standardization of this test has shown good reliability and validity in Iran (Cronbach’s alpha = 0.98) [44].

Hamilton Rating Scale for Depression (HRSD) The Hamilton Rating Scale for Depression (HRSD) is a 24-item scale that evaluates different aspects of depression (mood and affect, thoughts, behavior, cognition, somatization, occupational and sexual problems, suicidal ideas and sleep disorder). Scores of 17–24, 25–30 and 31 and above represent mild, moderate and severe depression, respectively. HRSD has been translated into Farsi and standardized for research [45]. The reliability coefficient of this test in Iran is 0.89 [46].

Barthel Index of Activities of Daily Living The Barthel Index of Activities of Daily Living (ADL) is a quantitative independency assessment tool that assesses the patient’s ability to take care of himself/herself. This index includes 10 common aspects of ADL, such as nutrition, bathing, bowel and bladder control, cleaning, wearing clothes and using the toilet. BI can be completed through a patient’s self-report or direct observation of his/her activities. Higher scores represent higher levels of functional independency. The implementation of this test is easy and takes little time [47–50]. This tool has been translated into Farsi and shows an appropriate reliability in Iran [51]. ▶ Table 1. The interpretation of the inventories are summarized in ●

Results

▼

59 individuals participated in this study, 25 women and 34 men. The mean age of these individuals was 67.6 ( ± 3.8) years. 17 cases were living in rural and 42 in urban areas. About 50 % of these individuals had undergraduate degrees. There was no significant difference in age, gender, the place of

residence (city or village), and educational level of the 3 study ▶ Table 2). groups (P > 0.05) (● 50 individuals (85 %) of these 59 participants had no history of depression and a family history of depression was negative in 90 % of them. There was no significant difference in the personal ▶ Table or family history of depression in the 3 groups (P > 0.05) (● 2). The distribution of MMSE scores and the distribution of depression severity of these 3 groups were the same (KruskalWallis P = 0.37 and P = 0.88, respectively). MMSE and HRSD were done at the beginning of the study and at weeks 2, 4, 8, and 12. There was a significant difference in HRSD in weeks 4 and 8 (ANOVA P < 0.001). Based on the Tukey test, the discrepancy of the results of the desipramine group with the 2 other groups has caused this difference. The skewness of the HRSD results of the desipramine group was more than the other ▶ Fig. 1). There was significant difference in the MMSE 2 groups (● scores of the 3 groups (ANOVA P = 0.035). The Tukey test showed that this difference is between the sertraline group and the ▶ Fig. 2). other 2 groups (● The Barthel test was done at the beginning of the study, at weeks 4 and 12. There was no significant difference between the scores ▶ Fig. 3). Based on within of the 3 groups (ANOVA P > 0.05) (● group comparison by paired T-test, the results of each group at follow-up were compared to baseline results. As presented ▶ Table 2, there was a significant difference between HRSD in ● scores at weeks 8 and 12, and the baseline of the sertraline group (P < 0.05). There was also a significant difference between HRSD scores at weeks 4 and 8, and the baseline of the venlafaxine group (P < 0.05), whereas there was no difference between baseline and end point scores (P > 0.05). Also, there was a significant difference between weeks 2, 4 and 8, and the baseline scores of the desipramine group (P < 0.05), but this difference did not exist at the end point (P > 0.05). In fact, the statistical analysis showed that only sertraline led to significant improvement of depression at the end of week 12. The skewness of improvement of the Hamilton test scores was relatively uniform. Although desipramine improved depression significantly after 2 weeks and had the fastest clinical response among these 3 drugs, this significant improvement of depression disappeared before week 12. As shown in the figures, in spite of the rapid improvement of skewness by week 8, the results of the Hamilton test worsened between weeks 8 and 12. In other words, desipramine treatment response was fast but temporary. Venlafaxine treatment response was seen by week 4, but by week 12 it became insignificant. In other words, venlafaxine treatment response was temporary and slower than desipramine, and became insignificant by week 12. The greatest improvement of Hamilton test scores in the venlafaxine group occurred between weeks 4 and 8. There was a significant difference between MMSE scores at the baseline and weeks 8 and 12

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**Dep = depression

134 Original Paper

Variables gender

Frequency sertraline venlafaxine desipramine total

residency

sertraline venlafaxine desipramine total

personal history of depression

sertraline venlafaxine desipramine total

family history of depression

sertraline venlafaxine desipramine total

age (mean ± SD)

education

sertraline venlafaxine desipramine total sertraline

venlafaxine

desipramine

total

female male female male female male female male rural urban rural urban rural urban rural urban − + − + − + − + − + − + − + − +

7 13 10 10 8 11 25 34 4 16 6 14 7 12 17 42 18 2 15 5 17 2 50 9 18 2 18 2 17 2 53 6

Percent 35.0 65.0 50.0 50.0 42.1 57.9 42.4 57.6 20.0 80.0 30.0 70.0 36.8 63.2 28.8 71.2 90.0 10.0 75.0 25.0 89.5 10.5 84.7 15.3 90.0 10.0 90.0 10.0 89.5 10.5 89.8 10.2

X2

P*

0.922

0.631

1.368

0.505

2.225

0.329

0.004

0.998

67.3 ± 3.0 67.9 ± 2.8 67.6 ± 5.3 67.6 ± 3.8 illiterate elementary under diploma diploma upper diploma illiterate elementary under diploma diploma upper diploma illiterate elementary under diploma diploma upper diploma illiterate elementary under diploma diploma upper diploma

of treatment in sertraline and venlafaxine groups (P < 0.05), unlike in the desipramine group. After about 8 weeks of treatment, sertraline and venlafaxine led to significant improvements of cognition and this lasted until week 12. The improvement of cognition was significantly higher in the sertraline group than the other 2 groups. According to the

2 4 9 4 1 2 1 11 5 1 5 4 8 1 1 9 9 28 10 3

0.391

10 20 45 20 5 10 5 55 25 5 26.3 21.1 42.1 5.3 5.3 15.3 15.3 47.5 16.9 5.1

P = 0.091

Barthel scores, there was a significant difference between the baseline and week 12 results (P < 0.05), but there was no difference between the baseline and week 4 results (P > 0.05). All 3 drugs improved patients’ daily functions significantly after 12 weeks. Functional improvement was greater in the venlafaxine group, but compared to the other 2 groups, this difference was

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Table 2 The demographic information of the study groups.

Original Paper 135

Fig. 1 Changes in HRSD scores during the study in the 3 groups (the asterisks denote the points in which a statistically significant difference with the starting point is seen) (Color figure available online only).

40

35

30

30.8947 30.65 30.6

30.1 28.3 26.1053

27.25

HRSD

25

27.5

21.9

20

19.6842

14.05

13.3158

13.8421

10

5 before

2nd week Desipramine

4th week

8th week

Venlafaxine

12th week

Sertaline

Fig. 2 Changes in MMSE scores during the study in the 3 groups (the asterisks denote the points in which a statistically significant difference with the starting point is seen) (Color figure available online only).

22

20

18.35

MMSE

18 16.7

15.9

16 15.1053 15.05 14.7

15.45 15.1053 14.7

15.2632 15.05 14.7

15.7 15.2632

15.7895

14

12

10 before

2nd week Sertraline

4th week Venlafaxine

8th week

12th week

Desipramine

▶ Table 3 compares MMSE, HRSD, and the Barnot significant. ● thel test scores in the 3 study groups at weeks 2, 4, 8, and 12. There was no significant difference in the effects of these 3 drugs on depression, cognition and functioning in women and men. The paired T-test comparison of the Hamilton test at the baseline and end point of the study showed P = 0.006 in women and P = 0.001 in men in the sertraline group. Also the comparison of MMSE scores at the baseline and end point of the study showed

P = 0.009 in women and P = 0.002 in men in this group. In other words, the anti-depressant and cognitive enhancing treatment responses were significant in both women and men. The paired T-test of MMSE scores at the baseline and end point showed P = 0.001 in women and P = 0.001 in men in the venlafaxine group. But the comparison of the Hamilton test at the baseline and end point of the study showed the same insignificant response (P = 0.63) in this group in both women and men.

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17

16.1

15

136 Original Paper

Fig. 3 Changes in the Bathel scores during the study in the 3 groups (the asterisks denote the points in which a statistically significant difference with the starting point is seen) (Color figure available online only).

19

18

17

16

17

16.1

15.7

15

14

14.6

14.2105 14.25

14.5263

13

12

11

4th week

before Sertraline

Venlafaxine

12th week Desipramine

Table 3 MMSE, HRDS, and the Barthel test scores of the study groups at weeks 2, 4, 8, and 12. P value MMSE

Sertraline

venlafaxine

desipramine

HRDS

sertraline

venlafaxine

desipramine

Barthel

sertraline venlafaxine desipramine

Before*2nd week before*4th week before*8th week before*12th week before*2nd week before*4th week before*8th week before*12th week before*2nd week before*4th week before*8th week before*12th week before*2nd week before*4th week before*8th week before*12th week before*2nd week before*4th week before*8th week before*12th week before*2nd week before*4th week before*8th week before*12th week before*4th week before*12th week before*4th week before*12th week before*4th week before*12th week

0.102 0.102 0.012 0.028 1.00 1.00 0.039 0.017 1.00 0.450 0.891 0.279 0.055 0.071 < 0.001 < 0.001 0.330 0.017 < 0.001 0.065 0.002 0.007 0.008 0.556 0.197 0.007 0.66 0.017 0.157 0.005

The most common side effects were headache and restlessness in the sertraline group, nausea and restlessness in the venlafaxine group, and drowsiness and dry mouth in the desipramine ▶ Table 4). group (●

Discussion

▼

The objective of this clinical trial was to compare the effects of sertraline, venlafaxine and desipramine on depression, cognition and the daily functioning of depressed Alzheimer patients. 12 weeks of follow-up showed that sertraline improved depression, cognition and daily functioning significantly; venlafaxine improved cognition and daily functioning; and desipramine improved only daily functioning.

Depression In our study, by the end of week 12, only sertraline was shown to have had a significant effect on depression. Although desipramine improved depression significantly after 2 weeks and showed the fastest treatment response among these 3 drugs, this significant improvement disappeared before week 12. Venlafaxine treatment response was seen by week 4. By week 12 it became insignificant. In other words, venlafaxine treatment response to depression was temporary and slower than desipramine, and it became insignificant by week 12. The most improvements in the Hamilton test scores in the venlafaxine group occurred between weeks 4 and 8. A review in 2010 and a meta-analysis in 2011 showed that both tricyclic antidepressants and SSRIs are superior to placebos in the treatment of depression. In some trials this difference was signifi-

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Barthel

15.7368 15.7

Original Paper 137

sleepiness

headache

severe xerostomia

nausea

vomiting

constipation

anorexia

tremor

restlessness

myoclonic jerks

insomnia

Group

Frequency

sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine sertraline venlafaxine desipramine

2 0 6 5 1 0 0 0 6 2 6 3 0 1 0 0 0 3 2 0 0 1 0 3 3 3 0 1 0 0 1 0 0

Percent 6.6 0 20.6 16.6 3.3 0 0 0 20.6 6.6 20.0 10.3 0 3.3 0 0 0 10.3 6.6 0 0 3.3 0 10.3 10.0 10.0 0 3.3 0 0 3.3 0 0

cant, but in others it was insignificant. Sertraline is one of the most commonly used drugs in this area [8, 52]. In our 12-week study, only sertraline showed a significant improvement in the treatment of depression at the end of week 12, and although a significant treatment response was elicited faster by tricyclic antidepressants, it was only temporary. In one study, the impact of venlafaxine antidepressant on the outcome of depression of dementia patients was similar to that of placebos [20]. In our study, a significant response was seen in week 4 and continued to week 8 in the venlafaxine group, but it did not last until week 12. In other words, there was a relative venlafaxine treatment response to dementia-related depression, but it was not permanent and became insignificant by week 12. A meta-analysis in 2007 showed that anti-depressants were superior to placebos in the treatment of depression in Alzheimer patients, but our study confirmed only the significant effects of sertraline [10]. Dementia decreases treatment response to antidepressants when compared to non-dementia related depression [53]. On the other hand, another study on patients with advanced Alzheimer showed that sertraline was not superior to placebos. This issue may also be generalized to desipramine and venlafaxine. Since our study population included only moderate severity dementia patients with major depression, the insignificant treatment response to venlafaxine and desipramine may be due to their moderate level of dementia, a stronger response might have been seen in mild dementia or MCI (mild cognitive impairment).

Proving these hypotheses requires further studies in this area; based on the available information, a verdict cannot be reached on this issue.

Cognition Our study showed that sertraline and venlafaxine improved cognition significantly, after about 8 weeks of treatment, and this improvement lasted until week 12. Comparing the 3 groups, improvement of cognition was significantly higher in the sertraline group. A study with the goal of examining the impact of antidepressants on cognitive functioning of the elderly with major depression, compared sertraline, fluoxetine and nortriptyline for 12 weeks. It showed that cognitive improvement was significantly related to the improvement of depression. This relationship had the highest degree of significance in sertraline, and lowest in fluoxetine. Furthermore, an acute improvement of depression was related to improvement of cognitive functioning. It should be noted that this study was carried out on the elderly without Alzheimer, but it showed that improvements in depression and cognitive functioning were closely correlated [41]. Another study showed that antidepressants improved cognition in some areas such as executive functions and attention in patients with some cognitive deficits but without dementia. The researchers indicated that lack of cognitive improvement after receiving antidepressants might be correlated to an increased risk of dementia [22]. It may be inferred that those patients in our study who received antidepressants but did not show cognitive functioning improvement, are more likely to progress into severe Alzheimer’s dementia. On the other hand, the results of a meta-analysis in 2007 suggested that there was not a significant difference between antidepressants and placebos in improving Alzheimer patients’ cognition [10]. Another study examined the cognitive effects of sertraline in comparison with placebos in Alzheimer patients with major depression. It showed that women who received sertraline showed a significant cognitive improvement in comparison with placebos, but such a difference was not observed in men [54]. In 2012, researchers studied the effects of 100 mg of sertraline, in comparison with placebos on the cognitive functioning of Alzheimer-related depression. They showed that antidepressant treatment and remission of depression, only led to mild general changes in cognition. Since the dosage of sertraline was increased up to 150 mg in some volunteers in our study, we may perhaps conclude that higher doses of sertraline may lead to more cognitive improvement, and that the observed difference is due to higher doses of sertraline in our study. Further studies still need to be carried out before deciding on this issue. A study that followed depressed Alzheimer patients receiving sertraline for 9 months showed that sertraline could play a role in protecting against the adverse cognitive effects of depression [55]. The importance of monoamines (including serotonin and norepinephrine) in cognitive functioning has been established. Venlafaxine, which affects monoamines, promotes memory in animal studies [56]. Likewise, our study confirmed the significant positive effects of venlafaxine on cognition.

Daily activities Our study showed that, after 12 weeks, venlafaxine, sertraline and desipramine improved patients’ daily functioning significantly. This improvement was higher in the venlafaxine group, but this difference was not significant.

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Table 4 Frequency of side effects in the study groups.

Consistent with our study, another study has shown that, in comparison with placebos, sertraline leads to improvement of daily activity assessment measures and decreases behavioral disorders [9]. In 2007, a study claimed that the impacts of venlafaxine and placebos on the outcome of depression, including the scores of Clinical Global Impression (CGI) (which shows the patient’s functional status), were similar [20]. However, in our study, all of these drugs led to improved daily functioning as assessed by the Barthel Index. It is possible that the observed difference between the results of our study and the mentioned study may be due to different assessment measures (CGI vs. Barthel).

Side effects In our study, the most common side effects were headaches and restlessness in the sertraline group, nausea and restlessness in the venlafaxine group, and drowsiness and dry mouth in the desipramine group. Reviews have shown that the most common side effects of SSRIs are digestive (especially nausea) and neuropsychiatric symptoms (especially headaches and tremors) [26]. Another study showed that in comparison with TCAs, SSRIs are better tolerated; however, nausea and vomiting may be problematic in elderly patients with dementia [24]. In a study in 2007, the side effects of venlafaxine were similar to those of placebos [20]. Patients on venlafaxine experience nausea, restlessness or dry mouth, which are generally mild and tolerable. Severe side effects are rare [57]. Studies show that in comparison with other tricyclic antidepressants, desipramine causes less drowsiness and anticholinergic properties [31]. In our study, drowsiness and dry mouth were more common than other side effects in the desipramine group, but they were mild and tolerable. Overall, similar to other studies, the severity of side effects was low in our participants and these side effects were not severe enough to cause medication discontinuation or require specific clinical attention.

Response to treatment in women vs. men In our study, anti-depressant and cognitive enhancing treatment responses in the sertraline group were significant in both women and men. But another study showed that women with Alzheimer who received sertraline showed significant cognitive improvements, while such improvements were not observed in men [54].

Although desipramine has minimal anticholinergic effects [30], it might affect cognitive function. However, a study in 2012 revealed that desipramine had neuro-protective and anti-apoptotic properties, and its effect on the neuro-degeneration process could make it a prime candidate in the treatment of AD-related depression [31]. The liver CYP-2D6 enzyme activity varies a lot in different individuals. This enzyme is responsible for metabolizing a wide range of commonly used drugs, such as antidepressants, anti-arrhythmics and beta-blockers. The speed of drug metabolism affects its plasma concentration. For instance, it decreases the serum level of venlafaxine and metoprolol in ultra-rapid metabolizers (Ums). Such individualized differences in drug metabolism may lead to undesired side effects or changes in expected clinical response [60]. Our results may have been affected by this issue. Predominant anhedonia, a decline in activities and indecision worsen the prognosis of antidepressant treatment of depressed patients and may require additional treatment [61]. Our treatment results may have also been influenced by these symptoms in some of our patients. Although there was no significant difference in the educational level of the 3 groups in our study (P > 0.05), within group heterogeneity in this regard could make for differences in response to treatment. So we suggest a larger sample size in future studies to compare the possible association of response to treatment with a patient’s educational level. Studies have also shown that the integrative approach, including antidepressants along with cholinesterase inhibitors, supplements, vitamins, and life style changes, may improve cognitive functioning of depressed elderly with dementia [62]. On the other hand, because of medical illnesses and conditions of the elderly with dementia, sometimes it may be difficult to implement this approach. We assigned the standard period of 12 weeks to follow-up in our study, a period that is considered appropriate for assessing the treatment responses of the elderly. However, because of the slow treatment responses of the elderly to antidepressant drugs [32], it may be better to extend the follow-up period in future studies in order to examine whether venlafaxine and desipramine treatment responses would increase significantly in a longer follow-up. Overall, concurring with some previous studies, our study showed that sertraline may be the best option in the treatment of depression in Alzheimer’s dementia [52]. Optimal antidepressant effects, its limited drug interactions, negligible side effects, and positive effects on patients’ cognition and daily functioning are the advantages of this treatment option.

Limitations

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Patients with dementia experience more psychiatric and medical co-morbidities than the elderly without dementia. Studies show that 60 % of geriatric patients with dementia experience at least 3 co-morbid diseases. Undoubtedly, some of these diseases require pharmacotherapy and drug interactions are sometimes inevitable. This may decrease (or make unpredictable) the efficacy of the drugs prescribed for co-morbid psychiatric disorders (such as depression), and might even lead to worsening of these disorders [52, 58]. Although in this study we tried to control some of these conditions, treatment with H2 blockers, anti-hypertensives, and cardiovascular and cholesterol-lowering drugs was continued inevitably. H2-receptor antagonists may affect liver metabolism and absorption and renal excretion of the drugs in our study [59].

Acknowledgements

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We would like to express our appreciation to the Vice Chancellor of Research of Mashhad University of Medical Sciences, Dr. Hadi Bakhti and staff of outpatient clinic of Ibn-e-Sina Hospital.

Conflict of Interests

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This research was performed after approval by research and ethical committees of the university. This research received a grant from Vice chancellor of research of Mashhad University of Medical Sciences. The authors had no conflict of interests with the results.

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