Efficacy of herbal combination of sedge, saffron, and Astragalus honey on major neurocognitive disorder

Abstract

Background
Major neurocognitive disorder (MCD) is an acquired progressive decline in cognitive abilities that causes a drop in specific acquired performance compared to former performances. We tried to investigate the efficacy of herbal combination of sedge, saffron, and Astragalus honey on cognitive and depression score of patients with MCD.

Materials and Methods
It was a randomized double-blind clinical trial conducted on sixty patients with MCD, who referred to the geriatric psychiatry clinic of Isfahan University of Medical Sciences in Iran. All the study participants had been using anti-MCD medications. Participants were randomized to receive a combination of sedge, saffron, and Astragalus honey in case group (n = 30) or placebo group for 8 weeks other than anti-MCD medications. Cognitive and depression scores were assessed using Addenbrook's Cognitive Scale and Geriatric Depression Scale, respectively, before intervention and at the 1st and 2nd months after intervention. The ANCOVA repeated-measure test was used to analyze the data using SPSS 20 software.

Results
The Addenbrook's Cognitive Test score was 32.2 ± 26.5 in intervention and 22.1 ± 15.1 in control group before intervention (P = 0.074) and 38.8 ± 27.7 in intervention group and 22.6 ± 14.1 in control group in control group 1 month after intervention (P = 0.007). In addition, Geriatric Depression Scale score was 14.6 ± 7.9 in intervention group and 14.5 ± 6.9 in control group before intervention (P = 0.945) and 12.9 ± 6.9 in intervention and 14.3 ± 7.1 in control group 1 month after intervention (P = 0.465) and 12.2 ± 6.5 in intervention group and 14.4 ± 7.1 in control group 2 month after intervention (P = 0.224).

Conclusion
Our findings suggest that adding the herbal combination of sedge, saffron, and Astragalus honey to the current protocols of treatment of MCD patients could be useful in the improvement of cognitive and depression score of these patients.

Full text

© 2018 Journal of Research in Medical Sciences | Published by Wolters Kluwer - Medknow | 2018 |
1
Efficacy of herbal combination of sedge, saffron,
and Astragalus honey on major neurocognitive
disorder
Shahla Akouchekian, Victoria Omranifard, Mohamad Reza Maracy, Ainour Pedram, Asiyeh Almasi Zefreh
Behaviour Science Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
induced, multiple etiologic, and unspecied dementia.[1]
The most common type of dementia is AD.[2]
Studies had shown that severity of dementia in AD
greatly depends on the increase of neurons in the nucleus
basalis of Meynert in brain which is accompanied with
a signicant reduction to the amount of acetylcholine
transfer enzyme.[3]
Due to the impairment in cognitive and global function
of patients with MCD, it may cause a huge catastrophic
disease burden on patients and may induce a heavy
psychological distress for their relatives and hence the
optimal treatment is highly critical.
INTRODUCTION
According to the Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition (DSM 5), major
neurocognitive disorder (MCD) is marked by severe
impairment in memory, judgment, orientation, and
cognition that is mostly acquired and not congenital.
There are several subtypes of MCD, namely Alzheimer’s
disease (AD), vascular dementia, frontotemporal lobar
degeneration, Lewy body disease, traumatic brain injury
from physical trauma, HIV disease, and Prion disease. Some
kinds that are caused by medical condition are Parkinson’s
disease, Huntington’s disease, substance/medication
Background: Major neurocognitive disorder(MCD) is an acquired progressive decline in cognitive abilities that causes a drop in
specific acquired performance compared to former performances. We tried to investigate the efficacy of herbal combination of sedge,
saffron, and Astragalus honey on cognitive and depression score of patients with MCD. Materials and Methods: It was a randomized
double‑blind clinical trial conducted on sixty patients with MCD, who referred to the geriatric psychiatry clinic of Isfahan University
of Medical Sciences in Iran. All the study participants had been using anti‑MC D medications. Participants were randomized to receive
a combination of sedge, saffron, and Astragalus honey in case group (n=30) or placebo group for 8weeks other than anti‑MCD
medications. Cognitive and depression scores were assessed using Addenbrook’s Cognitive Scale and Geriatric Depression Scale,
respectively, before intervention and at the 1stand 2ndmonths after intervention. e ANCOVA repeated‑measure test was used to
analyze the data using SPSS 20 software. Results: e Addenbrook’s Cognitive Test score was 32.2±26.5 in intervention and 22.1±15.1
in control group before intervention(P=0.074) and 38.8±27.7 in intervention group and 22.6±14.1 in control group in control
group1month after intervention(P=0.007). In addition, Geriatric Depression Scale score was 14.6±7.9 in intervention group and
14.5±6.9 in control group before intervention(P=0.945) and 12.9±6.9 in intervention and 14.3±7.1 in control group1month after
intervention(P=0.465) and 12.2±6.5 in intervention group and 14.4±7.1 in control group2month after intervention(P=0.224).
Conclusion: Our findings suggest that adding the herbal combination of sedge, saffron, and Astragalus honey to the current protocols
of treatment of MCD patients could be useful in the improvement of cognitive and depression score of these patients.
Key words: Astragalus plant, cognition, cognitive disorders, mental status tests
Address for correspondence: Dr. Ainour Pedram, Behaviour Science Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
E‑mail: pedramainour95@gmail.com
Received: 12‑11‑2017; Revised: 11‑02‑2018; Accepted: 27‑03‑2018
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DOI:
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How to cite this article: Akouchekian S, Omranifard V, Maracy MR, Pedram A, Zefreh AA. Efcacy of herbal combination of sedge, saffron, and Astragalus
honey on major neurocognitive disorder. J Res Med Sci 2018;23:58.
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Akouchekian, et al.: Herbal medications in neurocognitive disorder
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The available documented treatments are by cholinesterase
inhibitors such as donepezil, rivastigmine, galantine,
and tacrine. These drugs reduce acetylcholine
neurotransmier inactivation and thus enhance cholinergic
neurotransmission.[4] The other effective drug called
memantine is a kind of neuroprotective drug and its
eective mechanisms include blocking NMDA glutamate
receptors from moderate‑to‑severe cases of the disease and
FDA approved.[5‑8]
Several herbal remedies have been used in the treatment of
cognitive disorders with variable results.[9‑11] Ginkgo biloba
L. with antioxidant properties showed eectiveness with
the mechanism of increasing the blood ow in the brain.[6]
It seems that those herbal remedies that contain antioxidant
properties could improve the brain blood ow and decrease
the degenerative process in the brain.
Honey contains a variety of enzymatic and nonenzymatic
antioxidants such as glucose oxidase, catalase, L‑ascorbic
acid, flavonoids, phenolic acids, carotenoids, organic
acids, amino acids, and protein.[7] Sedge rhizome is rich
in natural antioxidants that can have a great important
therapeutic impact on the aging process and free radicals
of the diseases related, such as neural degeneration.[12,13]
Studies demonstrated that methanolic extract of this
herb strongly prevents the acetyl cholinesterase enzyme
activity.[14] Saron also contains crocin and safranl which
can reduce the harmful eects of hyoscine on memory
and enhance learning. Saron extracts contain abundant
carotenoids with strong antioxidant eects and can protect
nerve cells in the central nervous system.[15,16]
There are some studies about the properties of sedge,
saffron, and honey in the improvement of memory
disorders.[17] Although the effect of these herbal
medications has been reported in dierent studies, the
combinatory eect has not been evaluated yet. Therefore,
we tried to investigate the effect of addition of the
combined extract with sedge, saron, and Astragalus
honey to common treatment to improve cognitive
function score and depression score in patients with
MCD. We tried to determine mean aention, memory,
uency, visuospatial function, and language scores, before
and after intervention and to compare them between
intervention and placebo groups.
MATERIALS AND METHODS
This study was a randomized double‑blind clinical trial,
which had been done on sixty previously diagnosed MCD
patients that referred to the geriatric psychiatry clinic of
Isfahan University of Medical Sciences (IUMS) between
2015 and 2017.
The denite diagnosis of MCD was done by an expert
psychiatrist based on DSM 5 criteria. The sample size was
assessed by the following formula: −
22 2
11 1
2
12
()
26
()
ZS S
XX
+=, but
due to the case drop possibility, we enrolled thirty patients
in each group. Patients were randomly allocated through a
random number table into two groups of intervention and
placebo as binary random blocks.
This research is approved by the ethics commiee of IUMS
(Research project number 395043; [IRCT20161030255N1]).
Wrien informed consent was taken from patients and
their family. Inclusion criteria were as follows: age
over 50 years, developing any form of mild‑to‑moderate
MCD according to psychiatric clinical interviews
and diagnostic criteria of DSM V,[1] and using routine
anti‑MCD drug treatment. The exclusion criteria were
those with intellectual disability and major psychiatric
diseases such as schizophrenia, previous history of
mood disorder, and taking other herbal medicines. The
intervention group received two capsules of combined
sedge and saron extract daily (each capsule containing
500 mg of sedge and 30 mg of saron extract) plus a
teaspoon of Astragalus honey (equal to 5 g in each take).
The placebo group received two daily placebo capsules
(containing starch) with a teaspoonful of rock candy
syrup (equivalent to 5 mg); the duration of therapy was
3 months. Both the active and placebo capsules were
made by pharmacology faculty of IUIMS. Both groups
received usual treatment of anti‑MCD medications.
The usual antidementia therapy includes acetylcholine
esterase inhibitors such as rivastigmine and donepezil and
galantamine and memantine. Addenbrook’s Cognitive
Examination (ACE) for patients’ cognitive assessment
and Geriatric Depression Scale (GDS) scale were assessed
before intervention, 1 month after intervention, and
2 months after intervention.
Variable assessment
ACE for patients’ cognitive assessment and GDS scale
for patients’ depression assessment in three phases of
preintervention and 1st and 2nd months of intervention were
used and the results were recorded. It should be noted
that in all the three sessions, the side eects of the herbal
compound (sedge, saron, and Astragalus honey), such
as gastrointestinal symptoms, diarrhea, rash, drowsiness,
skin discoloration, blood in the urine, and medicinal plants’
interferences with the chemical drugs, were evaluated,
reported, and recorded.
ACE, revised version (ACE‑R): This test is a concise test
used to diagnose and classify all forms of dementia,
particularly AD and frontal temporal dementia. This test
consists of five subtests in which each of the subtests
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Akouchekian, et al.: Herbal medications in neurocognitive disorder
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3
evaluates one part of cognitive function. The maximum
score on the test score is 100, subscores are as follows:
attention/orientation (18 points), memory (26 points),
uency (14 points), language (26 points), and visuospatial
function (16 points).[18] Validity and reliability of the Farsi
version of this scale were reported by Pouretemad in 2007,
respectively, as 0.93 and 0.91.[19]
GDS is a self‑reported test of thirty questions. The GDS is
a standard self‑report test which can be used in patients
without severe intellectual disability and major psychiatric
diseases.
Yesavage et al. (1982) have designed this scale for
measurement of elderly depression. Test–retest reliability
and internal consistency of this scale in dierent researches
are reported, respectively, as from 0.85 to 0.90 and from 0.89
to 0.94. Cuing point to the scale is a score of 16.5 (sensitivity
0.88 and specicity 0.87); also, in Iran, Amini et al. in a study
reported the alpha coecient of the scale to be 0.75 and the
reliability coecient of split‑half scale to be 0.77.[20]
Medications were prescribed by a psychiatrist who were
unaware of patients’ allocation. Therefore, the patients
received the boxes including medication and placebo
which had specic codes. The patients were also unaware
of their allocation groups. Measurements were done by a
psychologist who was unaware of the patients’ groups. In
addition, the person who analyzed the data was unaware of
the patients’ group and data analysis was done using codes.
Statistical analysis
Data analysis was performed using IBM SPSS Statistics
for Windows, Version 20.0. (Armonk, NY: IBM Corp), and
descriptive tests (mean and standard deviation) were
performed to describe the participants’ demographic
characteristics. Furthermore, repeated‑measures ANCOVA
was performed for comparison of two groups (intervention
and placebo groups) in three times (baseline and after
1 month and 2 months). Simultaneously in a model, age
and education (conict variables) were controlled. Model
assumptions such as consequence normality, variance,
and covariance normality of questions were investigated.
P < 0.05 was considered statistically signicant.
RESULTS
Data related to sixty patients who remained in the study
were analyzed [Figure 1]. Results showed that the mean
age of patients in the intervention group was 66.8 years
and that of the placebo group was 70.2 years. The
intervention group had a higher educational background
than the placebo group which was considered in the further
analysis. [Remaining details are shown in Table 1].
Results of statistical tests [Table 2] show that
aention (P = 0.006), memory (P = 0.004), language (P = 0.009),
and visuospatial function (P = 0.015) are statistically
signicant in the intervention group, but uency variable
is not signicant in the intervention group (P = 0.289). In
total, Addenbrook’s score in the intervention group was
statistically signicant (P = 0.001) [Table 3].
The results of Mini–Mental State Examination (MMSE) scores
in intervention group were statistically signicant (P = 0.001),
and also GDS scores during intervention were statistically
signicant in the intervention group (P = 0.004).
DISCUSSION
Main study results
In this study, we evaluated the eect of adding sedge with
honey and saron to routine anti‑MCD medications of patients
with MCD. The eect was determined in 1 month and 2 months
after starting the intervention. The eect was evaluated using
Addenbrook’s Cognitive Scale, MMSE, and GDS.
The results of our intervention showed signicant increase
in all items of Addenbrook’s Cognitive Scale in the
intervention group in comparison to the control group
except uency, which was also signicantly higher in the
intervention group after 2 months of follow‑up. The items
of these test include aention, memory, uency, language,
and visuospatial function. The fluency score was not
signicantly dierent in two groups at 1‑month follow‑up.
Furthermore, we reported signicant increase in MMSE in
1‑ and 2‑month follow‑ups. The GDS was not signicantly
dierent in two groups.
Figure 1: The consort ow diagram of the study
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Akouchekian, et al.: Herbal medications in neurocognitive disorder
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In summary, we observed the benets of adding sedge
with honey and saron to routine anti‑MCD medication
of patients with MCD.
Role of honey in neurocognitive disorders
Some researchers have assessed the mechanism of action
of honey in brain tissue. Oyefuga et al. in 2012 showed
that usage of 250 mg honey causes a reduction of lipid
peroxidation in the brain tissue and simultaneous
reinforcement of superoxide dismutase and activities of
glutathione reductase;[10] also Cia in his research in 2011
concluded that honey reduces the number of degenerating
nerve cells in the CA1 region of the hippocampus, an area
that is too much prone to oxidative stress.[21] Al‑Rhbi in a
study in 2014 showed that honey has a signicant impact
on short‑ and long‑term memory.[22] In another study of
Akhondzadeh et al., on 55 patients with dementia, the
authors concluded that 30 g of honey in a day can be as
eective as donepezil for patients with mild dementia.[23] In
2009, in one of the British universities, British researchers
studied the cognitive function improvement on 212 patients
with dementia who were treated by honey and saron
supplement; within 8 weeks, signicant improvement
in sleep and memory of patients was observed that was
statistically signicant. It was also shown that with longer
treatment time, even up to 2 years, the recovery rate will
also increase.[24]
Role of sedge in neurocognitive disorders
Since this study is a new research with innovation,
unfortunately, clinical trials related to sedge are very
low and have been done on animals. Among these trials,
these studies can be mentioned; Rabie et al . found that
sedge rhizome extract in rats, by preserving the changes
in brain acetylcholine levels, signicantly improved motor
coordination.[20] Golghermezi and Nasri in 2015 found
that sedge rhizome has no signicant eect in improving
learning ability of treated mice group. Intraperitoneal
injection of sedge rhizome extract increases the recall rate.
However, its positive impact on long‑term memory is more
than the short‑term memory.[11]
Role of saron in neurocognitive disorders
For studies in line with saron, the following studies can
be mentioned. A study by Geromichalos in 2012 showed
that saron can improve physical activity by 30% and
acetylcholine in patients with dementia.[17] Akhondzadeh
et al. showed that 3‑week treatment with saron improved
cognitive performance of rats.[23] In another study of
Hosseinzadeh et al. in 2004, the authors found that saron
can be as eective as uoxetine in mice, and Noorbala et al.
conducted a similar study in 2005 and achieved the same
eect. In the meantime, Akhondzadeh et al. stated that
saron can be eective in mild depressed patients.[23‑25]
Moosavi also in 2014 stated in his research that 30 mg
uoxetine per day with 80 mg of saron, during 6 weeks
on depressed patients, can have a relatively beer eect
than saron alone. In another study in 2015, Moosavi et al.
showed that 15 mg saron per day and 15 g crocin per
day can cause good tolerance without complications for
patients.[26] Hosseinali et al. also stated in their study in 2013
that 50–250 mg saron per day causes increased dopamine,
but without eect on serotonin and norepinephrine.[27]
Study limitations
Our study had several limitations. As mentioned before
in the results’ section, the percentage of patients in
intervention group who had higher educational levels was
higher in comparison to that of the control group. However,
we had randomly assigned patients to intervention and
control groups, but the dierence in educational level was
signicant. To address this issue, we have used analysis
of covariances. However, it should be considered that this
eect may inuence our study results.
Table 1: Comparison of demographic characteristics in
patients with major neurocognitive disorder with respect
to the intervention and placebo groups
Characteristics Intervention Placebo P
Age (years), mean±SD 66.8±10.6 70.2±15.5 0.331
Child (n), mean±SD 4.3±1.6 4.9±1.6 0.168
Sex, n (%)
Male 17 (56.7) 15 (50.0) 0.605
Female 13 (43.3) 15 (50.0)
Education, n (%)
Elementary and secondary 14 (46.7) 24 (80.0) 0.007
Academic 16 (53.3) 6 (20.0)
Job, n (%)
Retired 19 (63.3) 12 (40.0) 0.194
Private 2 (6.7) 3 (10.0)
Housekeeper 9 (30.0) 15 (50.0)
Hand, n (%)
Right 30 (100) 28 (93.3) 0.246
Left 0 2 (6.7)
Hypertension, n (%)
Yes 14 (46.7) 10 (33.3) 0.292
No 16 (53.3) 20 (66.7)
MI, n (%)
Yes 8 (26.7) 4 (13.3) 0 .19 7
No 22 (73.3) 26 (86.7)
Neurosurgery, n (%)
Yes 4 (13.3) 1 (3.3) ‑
No 26 (86.7) 29 (96.7)
CVD, n (%)
Yes 1 (3.3) 1 (3.3) 1
No 29 (96.7) 29 (96.7)
Diabetes, n (%)
Yes 9 (30.0) 8 (26.7) 0.774
No 21 (70.0) 22 (73.3)
The results are presented as mean±SD or n (%) where applicable.
CVD=Cerebrovascular disease; MI=Myocardial infarction; SD=Standard deviation
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5
Another limitation of our study was sample size. Due to a
few number of study participants, the study was done in
few number of patients. This may cause the dierence in
educational level between two groups. Also, the study had
a new topic and only a few randomized controlled trials
were available.
Recommendations
Based on the ndings of our study, we recommend studies
with higher sample sizes which is needed to minimize
the difference in baseline characteristics between the
two groups. For achieving the higher sample sizes,
we recommend larger multicentric studies. Also, we
recommend more studies in this topic to achieve more
valuable evidences about the role of herbal medications
in the treatment of MCDs.
CONCLUSIONS
Our study has shown the benecial eects of sedge with
honey and saron in the treatment of MCDs. However,
more studies are needed to conrm these results.
Acknowledgments
At the end, it is essential to give my thanks and gratitude to
IUMS, all professors who helped me in this maer, as well
Table2:Summaryresultsofvariablesofattention,memory,uency,language,andvisuospatialfunctioninthree
stages
Variables Time Mean±SD P‡Effect size
Intervention (n=30) Control (n=30)
Attention Before (t0)8.3±6.1 5.6±4.0 0.055
After 1 month (t1)9.6±6.1 5.9±3.6 0.006
After 2 months (t2)9.8±6.1 5.6±3.6 0.002
Follow‑up effect in each group PΩ0.476 0.975
Follow‑up effect P£0.958 0.001
Main effect P£0.006 0.138
Memory Before (t0)5.1±5.7 3.1±3.4 0.087
After 1 month (t1)6.8±6.6 3±2.9 0.006
After 2 months (t2)7±6.8 3.1±2.9 0.006
Follow‑up effect in each group PΩ0.07 0.654
Follow‑up effect P£0.712 0.014
Main effect P£0.004 0.169
Fluency Before (t0)1.4±2.4 0.3±0.7 0.016
After 1 month (t1)1.8±2.5 0.7±1.5 0.052
After 2 months (t2)2±2.9 0.4±0.8 0.005
Follow‑up effect in each group PΩ0.117 0.973
Follow‑up effect P£0.381 0.002
Main effect P£0.289 0.025
Language Before (t0)10.6±8.7 8.6±5.6 0.312
After 1 month (t1)13±8.7 8.9±6 0.037
After 2 months (t2)13.5±8.7 9.3±6 0.035
Follow‑up effect in each group PΩ0.694 0.897
Follow‑up effect P£0.856 0.001
Main effect P£0.009 0.088
Visual Before (t0)6.5±5.6 4.3±3.5 0.073
After 1 month (t1)7.4±5.4 4.3±3.4 0.010
After 2 months (t2)7.1±4.9 4.3±3.4 0.012
Follow‑up effect in each group PΩ0.089 0.591
Follow‑up effect P£0.443 0.025
Main effect P£0.015 0.036
Total Before (t0)32.2±26.5 22.1±15.1 0.074
After 1 month (t1)38.8±27.7 22.6±14.1 0.007
After 2 months (t2)39.4±27.7 22.2±14.5 0.004
Follow‑up effect in each group PΩ0.329 0.635
Follow‑up effect P£0.271 0.023
Main effect P£<0.001 0.205
(Addenbrook’s Cognitive Tests) using ANCOVA repeated‑measures. ‡t‑test; ΩRepeated‑measure test stratied by group controlling baseline and age; £ANCOVA repeated‑measures
test controlling for age and education. SD=Standard deviation
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Akouchekian, et al.: Herbal medications in neurocognitive disorder
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as patients and their families for their sincere cooperation
in this study.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
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Table 3: Analysis of variance of Mini‑Mental State Examination and Geriatric Depression Scale at three stages of the
test
Variables Time Mean±SD P‡Effect size
Intervention (n=30) Control (n=30)
MMSE Before (t0)13.5±9.8 10.4±6.9 0.163
After 1 month (t1)16.5±9.4 10.1±6.5 0.004
After 2 months (t2)16.8±9.3 10.3±6.7 0.003
Follow‑up effect in each group PΩ0.059 0.910
Follow‑up effect P£0.405 0.013
Main effect P£<0.001 0.251
GDS Before (t0)14.6±7.9 14.5±6.9 0.945
After 1 month (t1)12.9±6.9 14.3±7.1 0.465
After 2 months (t2)12.2±6.5 14.4±7.1 0.224
Follow‑up effect in each group PΩ0.604 0.507
Follow‑up effect P£0.547 0.006
Main effect P£0.004 0.112
‡t‑test; ΩRepeated‑measures test stratied by group, controlling baseline and age; £ANCOVA repeated‑measures test controlling for age and education. SD=Standard deviation;
GDS=Geriatric Depression Scale; MMSE=Mini‑Mental State Examination
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Akouchekian, et al.: Herbal medications in neurocognitive disorder
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