Download Lower Side Effects of Milnacipran than Paroxetine in the Treatment

Chinese Journal of Physiology 51(6): 387-393, 2008
387
Lower Side Effects of Milnacipran than
Paroxetine in the Treatment of Major
Depression Disorder among Han Chinese
in Taiwan
– i Lêng 2, 3, Jo Yung-Wei Wu2, Sheng-Yu Lee 1, 4,
Ting-Ting Chang 1, Chhian-Hu
4
Yu-Shan Wang , Yi-Chyan Chen5, and Ru-Band Lu 1, 2, 4
1
Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University
Tainan 704
2
Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University
Tainan 704
3
Department of Public Health, Chung Shan Medical University
Taichung 402
4
Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University
Tainan 704
5
Department of Psychiatry, Tri-Service General Hospital
Taipei 114, Taiwan, Republic of China
Abstract
Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine
reuptake. To our knowledge, it has limited affinity for most monoamine neurotransmitter receptors.
With limited pharmacokinetic interaction with the cytochrome 450 system, milnacipran may have a low
risk in drug interaction. The present study compares milnacipran with paroxetine, a selective serotonin
reuptake inhibitor (SSRI) and which has been used clinically for years to evaluate the efficacy, patient
tolerance, and side effects in the treatment of major depression. The study took place in two medical
centers located in Northern and Southern Taiwan. Six-three participant who met the Diagnostic and
Statistical Manual of Mental Disorder 4th edition (DSM-IV) criteria for a major depressive disorder and
a total Hamilton Depression Rating Scale (HAM-D) score ≥ 16 on the 17 item scale, were recruited.
Participants first received either 100 mg/day of milnacipran (33 participants) or 20 mg/day of paroxetine
(30 participants), and were then assessed with HAM-D and clinical global impression scale (CGI) for
severity of the illness and global improvement, at the beginning and the end of the first, second, fourth,
and eighth weeks of the drug treatment. Thirty-eight patients with major depressive disorder completed
the study. No statistically significant differences were observed between the two groups in the reduction
of HAM-D and CGI scores. However, side effects such as headache and tremor in the first week,
psychomotor retardation and difficulty in concentration in the fourth week, and psychomotor retardation
in the eighth week of treatment were significantly lower in the milnacipran group, as compared to that
of the paroxetine group. We concluded that milnacipran and paroxetine had similar clinical effectiveness
during the eight-week treatment of major depressive disorder. Further investigation is needed to
examine the clinical suitability of this drug for patients with liver impairments and for elderly patients
suffering from major depression.
Key Words: milnacipran, paroxetine, major depression, efficacy, side effect
Corresponding author: Dr. Ru-Band Lu, Dept. of Psychiatry, National Cheng Kung University Hospital, No. 138, Sheng Li Road, Tainan
70428, Taiwan, R.O.C. Tel: +886-6-2353535 ext. 5108, Fax: +886-6-3028012, E-mail: [email protected]
Received: January 30, 2008; Revised (Final Version): June 20, 2008; Accepted: July 1, 2008.
2008 by The Chinese Physiological Society. ISSN : 0304-4920. http://www.cps.org.tw
388
Chang, L êng, Wu, Lee, Wang, Chen and Lu
Introduction
NH2
NEt2
Depression is one of the most common psychiatric
disorders. Cross-sectional studies have found that
the world wide prevalence is about 3% (8); the lifetime
prevalence of major depression is about 15% and may
increase up to 25% in women (26). The disorder has
a high rate of recurrence (1) and suicide (19). Major
depression disorder usually occurrs between 30 and
50 years of age (30), but only 5%-10% of patients
would receive adequate treatment (8). This is a major
health problem. In modern psychiatry, there are several
unresolved controversies regarding its characteristics
such as its etiology and treatment.
Based on previous studies, major depression is
caused by low levels of certain neurotransmitters in
the central nervous system, mainly serotonin and
norepinephrine (7, 32). In the past 40 years, imipramine
(6) and TCAs (tricyclic antidepressants) such as
mitriptyline, nortriptyline, and desipramine have been
proven to be effective treatment agents for most major
depressive patients. However, these agents have serious
side effects (dizziness, dry mouth, nausea, constipation,
and palpitations), which may affect the daily activities
and social functions of patients, further influencing
drug compliance.
Recently, selective serotonin reuptake inhibitors
(SSRIs) and serotonin- norepinephrine reuptake
inhibitors (SNRIs) have become the most commonly
prescribed antidepressants. These antidepressants
are characterized by a more favorable effect profile,
simpler dosing, and less anticholinergic effects than
TCAs (13, 36). However, TCAs, SSRIs, and SNRIs
all need to be metabolized by cytochrome P450
(CYP450) enzymes in the liver. Thus, the prescription
of antidepressants becomes a challenge for clinicians
when considering the common comorbid liver
dysfunction among the Asian population.
The chemical structure of milnacipran is (1R, 2R)2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane1-carboxamide (Fig. 1), which is a new antidepressant
with selective serotonin and norepinephrine reuptake
inhibitor (SNRIs) properties and has no interaction effect
on the post-synaptic receptors or ion channels and, in
particular, limited cholinergic, histaminergic and alpha1adrenergic effects (3, 21). Milnacipran is rapidly and
extensively absorbed by oral administration and is not
affected by food intake. Maximum plasma concentrations
are reached approximately two hours after oral drug
administration. Milnacipran lacks the first-pass
effect and the bioavailability is approximately 85%. It
has a low affinity (only 13%) for plasma proteins.
Milnacipran does not require CYP450 enzyme-mediate
a
O
Ph
Fig. 1. Chemical structure of milnacipran.
biotransformation. Rather, it is mainly metabolized
by glucuronic acid conjugation and does not give rise
to an active metabolite. Furthermore, elimination occurs
mainly via the kidney with tubular secretion of the
product in its unaltered form (3).
On the other hand, paroxetine has been used
clinically for years. As an SSRI, it not only acts on
norepinephrine transporter but also inhibits norepinephrine reuptake, which is far more extensive than other
SSRIs (2). It functions as a highly selective antagonist
of the serotonin transporter as well as an inhibitor of
the norepinephrine transporter enzyme. Paroxetine
can inhibit the reuptake of both norepinephrine and
serotonin (20), which is the reason why previous
studies have often compared paroxetine with other
SNRI for a further understanding on their clinical
efficacy and side effects (34). It has a high inhibition
potential at CYP450 enzyme systems, and it is the
most potent for 2D6 inhibition. Much of paroxetine
in serum is protein bound. It is one of the most
frequently prescribed antidepressants used worldwide.
The present study has been designed to compare
the clinical efficacy, tolerance, and side effects of
milnacipran and paroxetine among patients with major
depression.
Materials and Methods
Sampling
Psychiatrists from two medical centers located
in Northern and Southern Taiwan selected patients
between the ages of 18-65 who met the DSM-IV
(Diagnostic and Statistical Manual of Mental Disorder
4th edition) a criteria for major depressive disorder,
including single or reoccurring disorder. All patients
were assessed with Mini-International Neuropsychiatric
Interview (MINI) (28) and carefully evaluated by trained
clinical psychologists. Patients who had a total Hamilton
Depression Rating Scale score ≥ 16 on the 17 item
scale (4) were recruited into the study. Female patients
were additionally assessed with the human chorionic
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Washington DC: American Psychiatric
Association, 1994.
Milnacipran and Paroxetine
389
Table 1. Clinical and demographic characteristics of acutely depressed patients treated with paroxetine or
milnacipran
Variable
Age
Gender
Male
Female
Height (cm)
Weight (Kg)
First depressive episode
Milnacipran
N = 33
Paroxetine
N = 30
P-value
49.58 ± 11.34
46.93 ± 9.71
0.21
10
23
161.63 ± 8.53
57.14 ± 12.99
27
12
18
163.20 ± 8.06
62.20 ± 10.13
21
0.60
gonadotropine (hCG) to exclude for pregnancy. Patients
were excluded if they had any of the followings: [1]
any comorbid psychiatric diagnosis, any medical or
neurological disease and physical disease requiring
treatment, [2] alcohol or substance dependence, [3]
any known hypersensitivity to milnacipran or paroxetine,
or a history of failure in MDD treatment with previous
use of electroconvulsive therapy (ECT). In addition,
patients must not have taken other antidepressants or
neuroleptics within a month, monoamine oxidase
inhibitors within 14 days, or other psychotropic drugs
within 7 days.
Procedures
This open label study began after receiving official
consent from the Institutional Review Board. Prior to
the study, informed consent was obtained from the
participants. All patients received physical examinations
and assessments on laboratory testing. The presence
of any abnormal findings on the physical examination
or laboratory testing would be reasons for exclusion.
Moreover, in this study we adopted the Hamilton
Depression Rating scale (HAM-D) as its efficacy
evaluation standard to observe would change before
and after treatment. At the baseline, patients were assessed
with the 17-item HAM-D, and the clinical global
impression scale (CGI) for the severity of illness and
global improvement; repeated measures were conducted
during the first, second, fourth and eighth weeks.
Patients were assigned to receive either 20 mg/
day of paroxetine or 50 mg/day of milnacipran (once
in the morning) for the first week and milnacipran 100
mg/day for the following weeks (50 mg in the morning
and 50 mg in the evening), for a total of eight weeks.
Dosage adjustment depending on the response or
tolerability was permitted throughout the treatment.
Additionally, if needed, benzodiazepine was prescribed.
All side effects that were observed during the experimental
session were noted in the Adverse Experience Report
(AER). The side effect assessments included the
0.49
0.12
0.27
followings: [A] Mental Status/6-item, [B] GenitoUrinary/4-item, [C] Cardiovascular/4-item, [D] HeadNeck/10-item, [E] Extremities/9-item, [F] Skin/4-item,
and [G] Gastrointestinal Tract/2-item. The severity
of side effects were divided into 4 degrees as follows:
0 = Not present; 1 = Mild or occasional; 2 = Moderate
or occurs several times a day; and 3 = Severe or persistent.
Statistical Analysis
Demographic and clinical characteristics of the
two treatment groups, such as gender and other variables
were examined using the Chi-Square ( χ 2) analysis.
Continuing variables such as age, depressive symptom
severity, clinical global impression scale (CGI) for
the severity of illness and global improvement, and
duration of depressive disorder were tested by Student’s
t test. Intragroup differences before and after treatment
were analyzed by paired t test, while intergroup
comparisons before and after treatment were tested
by student’s t analysis. The rate of respondents, defined
as patients who had at least a 50% decrease in the
HAM-D scores at the end point was compared between
treatment groups by a Chi-square (χ2) test. Side effects
were examined by Chi-square test and corrected by
Fisher’s exact test when the numbers were smaller
than four. The statistically level of significance was
P < 0.05.
Results
Initially 63 patients were recruited in entered
the study, and a final total of 38 patients with major
depressive disorder (19 patients in each group)
completed the eight week open-label treatment. There
was no significant difference between the initial study
groups in age, gender, and number of depressive
disorder (Table 1). All patients had no significant
medical problems and met DSM-IV criteria for a
major depressive disorder with a score ≥ 16 on the 17
390
Chang, L êng, Wu, Lee, Wang, Chen and Lu
Table 2. Mean HAM-D scores in patients with major depressive disorder at baseline and during 8 weeks of
treatment with milnacipran and paroxetine
Baseline
Week 1
Week 2
Week 4
Week 8
Milnacipran
Mean (SD)
Paroxetine
Mean (SD)
22.12 (4.15)
(N = 33)
12.41 (3.99)
(N = 24)
9.78 (4.55)
(N = 19)
16.20 (7.23)
(N = 30)
12.12 (9.6)
(N = 24)
16.41 (4.94)
(N = 29)
11.23 (4.59)
(N = 21)
22.73 (5.63)
(N = 30)
14.31 (7.51)
(N = 29)
8.47 (8.07)
(N = 19)
item Hamilton Depression Rating Scale.
A total of fourteen patients dropped out from
the 33 in the milnacipran group (42%), and 11 dropped
out from the 30 in the paroxetine group (36%), yielding
a total withdrawal of 25 patients (40%) from the
study. No significant differences were found between
the drop-out rates of the two groups (P = 0.64). Main
drop-outs were due to incompliance to the medication,
refusal to continue the study, and unwillingness to
revisit the hospital even after telephone tracing (9
patients, 36%). The secondary cause of drop-outs
were due to the patients’ intolerance of the side
effects (5 patients, 20%), lack of efficacy (2 patients,
8%), other personal issues (2 patients, 8%), or lost of
contact due to incorrect phone number and address (7
patients, 28%). There was no significant difference
in the demographic data between the dropped-out and
non-dropped-out participants.
The depressive symptoms of both groups had
significant improvements (P < 0.0001) during the 8
week treatment, decreasing HAM-D to an average
score of less than 10 after 8-weeks. Therefore,
paroxetine and milnacipran were effective in the
treatment of major depression.
In addition, there were no significant differences
when comparing the efficacies between both groups,
regardless of the weekly HAM-D average scores (Table
2, Fig. 2) and the clinical global impression scale (CGI)
for the severity of illness and global improvement
(Table 3). When comparing the number of respondents
between the two groups, defined as a decrease of at
least 50% in the HAM-D scores, the milnacipran group
had a total of 12 respondents (63%), while the
paroxetine group had a total of 16 respondents (84%).
No significant difference was found between the two
groups (P = 0.14).
Although the paroxetine group reported more
side effects than the milnacipran group in the first
25
P-value
0.62
0.89
0.24
0.69
0.54
milnacipran
paroxetine
Mean HAM-D Score
Visit
20
15
10
5
0
0
1
2
4
8
Time (weeks)
Fig. 2. Total HAM-D score and mean score of the treatment
population: intention for treatment
week, that is, the average reported number of side
effects equaled 5.58 versus 3.62 per person, respectively;
the difference was not statistically significant. No
significant differences were observed in the side effects
on the genitor-urinary, cardiovascular and dermatological
systems between the two groups. However, the
milnacipran treated patients had fewer side effects
including headache (Fisher’s Exact Test, P = 0.01)
and tremor (P = 0.01) in the first week, difficulty in
concentration and psychomotor retardation (P = 0.04
and P = 0.04 respectively) during the 4th week, and
psychomotor retardation (P = 0.03), forgetfulness of
simple things (borderline significant P = 0.05) in the
8th week of treatmen, as compared with the paroxetine
treated patients. Milnacipran yielded fewer side effects
in the four follow-up phases (Table 4). When patients
were treated with milnacipran, more nausea and vomiting
were clinically found, but there was a lack of statistical
significance between the two groups. These side effects
were more severe during the initial treatment phase,
Milnacipran and Paroxetine
391
Table 3. Mean Clinical Global Impression-Improvement (CGI-I) and Clinical Global Impression-Severity
(CGI-S) scores in patients with major depressive disorder at baseline and during 8 weeks
Visit
CGI-I
CGI-S
Milnacipran
Mean(SD)
Paroxetine
Mean(SD)
P-value
Baseline
Week 1
Week 2
Week 4
Week 8
2.86(1.06)
(N = 29)
3.21(0.88)
(N = 24)
3.76(0.54)
(N = 21)
3.63(0.68)
(N = 19)
2.77(0.90)
(N = 30)
3.48(0.87)
(N = 29)
3.71(0.95)
(N = 24)
3.58(0.84)
(N = 19)
0.71
0.26
0.81
0.83
Milnacipran
Mean(SD)
4.67(0.56)
(N = 33)
3.62(1.01)
(N = 29)
2.79(0.93)
(N = 24)
2.48(0.98)
(N = 21)
2.21(0.98)
(N = 19)
Paroxetine
Mean(SD)
4.67(0.80)
(N = 30)
3.43(1.28)
(N = 30)
3.10(1.37)
(N = 29)
2.54(1.74)
(N = 24)
2.11(1.33)
(N = 19)
P-value
0.60
0.54
0.33
0.88
0.79
Table 4. Less side effects yielded by milnacipran in the four follow-up phases in comparison to paroxetine
Visit
Week 1
(N = 41)
Week 4
(N = 31)
Week 8
(N = 29)
Side Effect (Fisher’s Exact Test, P-value)
headache (P = .01)
tremor (P = .01)
difficulty in concentration (P = .04)
psychomotor retardation (P = .04)
forgetful to simple things (P = .05)
psychomotor retardation (P = .03)
but gradually subsided with the ongoing of treatment.
Discussion
In this study, milnacipran and paroxetine were
found to have similar effects on treating major
depression. Similar to Sechter’s findings (27), there
was no difference between the 17-item HAM-D, CGII, and CGI-S among the two groups in the present
study, indicating that multiple comparisons may
increase type I and type II errors due to the small
sample size (19 patients each in both groups). To
obtain significant results, we will increase the sample
size in future studies.
Based on previous studies, paroxetine, as an SSRI,
has a high binding affinity with CYP450 (5, 35). In
contrast, milnacipran metabolism does not involve the
CYP450 enzyme system. For patients who need to
receive long-term depressive treatments, milnacipran
may have less influence on their liver and limit the
affect of drug-to-drug interaction. Several limitations
should be noted in the present study which includes
the small sample size in this open study: the lack of
b
excluding patients with liver and renal impairments,
and the lack of comparison between glutamyl
oxaloacetic transaminase (GOT) and glutamyl pyrubic
transaminase (GPT) plasma level before and after
treatment. To prove that milnacipran has fewer effects
on the patients’ liver function, we will increase the
sample size and laboratory data in future studies.
Previous studies have also shown that antidepressants appear to have similar treatment efficacy b
with varying side effects. Therefore, since milnacipran
and paroxetine have parallel mechanisms, both acting
as inhibitors in the reuptake of norepinephrine and
serotonin (20, 21), the main purpose was to compare
the differences of their side effects. We found that
paroxetine caused more side effects such as headaches,
tremor, difficulty in concentration, psychomotor
retardation, and forgetfulness of simple things than
milnacipran during the different treatment weeks. Such
differences may be due to the association of paroxetine
antihistamine and anticholinergic effects. Generally,
doctors would need to consider the drug compliance
and low incidence of side effects of antidepressants
(12) for patients who have a long-term treatment for
American Psychiatric Association. Practice guideline for major depressive disorder in adults. Am. J. Psychiatry. 150 Suppl. 4: 1-26, 1993.
392
Chang, L êng, Wu, Lee, Wang, Chen and Lu
depression for at least 6-9 months (15). The side effects
of antidepressants have become one of the critical factors
in drug complaints during treatment (15). Although
this study did not illustrate that patients had a better
tolerance with milnacipran than paroxetine, the findings
remain worthy of long-term follow-up.
During the first day of this study, three people
withdrew from this study due to nausea and vomiting
after taking 50 mg of milnacipran. Therefore, in the
future, studies adopting a lower dosage level in the
initial treatment such as 25 mg/day in the initial days
would be more appropriate. Moreover, previous studies
have indicated that there was no significant difference
in the efficacy between depressive patients receiving
either 50 mg/day or 100 mg/day milnacipran for an 8week treatment (18). Additionally, studies have also
reported that the psychotropic drug dosage of the
Han Chinese were generally lower than that of the
Caucasians (10, 13, 25). Due to such discrepancies
among different ethnic groups, in the future, it may
also be worthwhile to conduct studies comparing the
efficacies of different dosages or to design pharmacokinetic studies on the Asian population to identify the
optimal dosage of our population.
One third of the participants dropped out from
this study in both the milnacipran and paroxetine groups.
Such ratio is similar to that of the previous antidepressant
studies conducted in Taiwan (36). Several depressive
patients took prescribed medication irregularly or the
patients refused regular outpatient clinical follow-ups
before the medication became effective. According
to our clinical experience, patients who had just been
diagnosed of depression often would refuse to be
followed-up. Rather, patients and their family members
would be willing to receive further treatment only when
patients’ depressive symptoms reoccur, get worse, or
when patients make suicidal attempts. Therefore, the
mental illness stigma in Taiwan society remains a major
problem that hinders and may even prohibit patients
from receiving proper treatment. Improving public
mental health education is necessary for psychiatric
patients to receive adequate assistance in mental health
services. Furthermore, in this study, approximately
73% of all cases would be defined as having the first
onset of a depressive disorder. An immediate followup with adequate treatment can achieve an effective
treatment in 70% - 80% of all cases within a few weeks.
Unfortunately, some patients choose to discontinue
the treatment because they remain skeptical about the
use of antidepressants or pharmaceutical agents. Thus,
improvement is needed in mental health education,
adequate treatment, and the decrease of side effects of
medication.
Milnacipran, known as a member of serotonin
and noradrenaline reuptake inhibitors (SNRI) (22, 33),
has neither affinity for presynaptic or postsynaptic
receptors nor interactions with ion channels, especially
the cholinergic, histaminergic, serotonergic and
adrenergic receptors. Moreover, not needing to
metabolize through the CYP450, it is more tolerable
and has been proven to have better efficacy than paroxetine
(16) among elderly patients with depression. A good
effect was also observed when treating patients combined
with impaired liver function (23) and post-stroke
depression (29). The average age in the milnacipran
group was a little higher than that of the paroxetine
group (49.58 ± 11.34 and 46.93 ± 9.71), but lacked
statistical significance. In sum, the advantage of fewer
drug interactions and side effects make milnacipran a
safer and more tolerable choice in the clinical practice
of treating patients with depression (3, 9, 24).
Acknowledgments
This study was supported in part by National
Cheng Kung University Project of Promoting Academic
Excellence and Developing World Class Research
Centers, Taiwan, Republic of China. The authors would
like to thank Ms. E. S. Wu, and Ms. F. S. Lin for their
assistance in data collection and processing.
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