Key words
crocus sativus
- fluoxetine - postpartum depression - saffron - SSRI
Introduction
Postpartum depression is a common and serious mental health problem that is associated
with maternal suffering and numerous negative consequences for offspring [1]. It has been reported that 10–15% of women suffer postpartum depression following
childbirth [2]. Postpartum depression can harm the mother and child relationship, which in turn
negatively impacts children in terms of nutrition and care, as well as physical and
mental development [3]. Self-esteem, childcare stress, life stress, social support, marital relationship,
infant temperament, marital status, socioeconomic status, unwanted pregnancy, previous
psychiatric disorder, method of childbirth, previous abortion and biological changes
are related to postpartum depression [2]. Etiologies of mood balance, depressive disorders in particular, are not completely
understood. However, substantial evidence has accrued that serotonergic systems play
a central role [4]
[5]
[6]
[7]. Selective serotonin reuptake inhibitors (SSRIs) are the first line of pharmacotherapy
in postpartum depression. Despite beneficial effects of SSRIs on depressive symptoms
in postpartum depression, rate of remission remains low and risk of relapse and recurrence
remains high [8]
[9]
[10]
[11]
[12]
[13]. Furthermore, most of these antidepressant agents produce several adverse reactions,
such as anticholinergic effects, orthostatic hypotension, arrhythmias and sexual dysfunction
[14]
[15]. Thus there is need for more effective and less toxic agents. Plant extracts are
some of the most attractive sources of new drugs and have shown promising results
for treatment of depression [16]
[17]. Saffron is produced from the tiny, dried stigma of lily-like Crocus sativus blossom [18]. In Asian medicine, and particularly in Persian traditional medicine, it is used
to treat menstrual disorder, difficult labor, inflammation, vomiting and diseases
affecting the throat [18]
[19]
[20]. Several controlled studies have shown beneficial effects of Crocus sativus on depression, premenstrual symptoms and Alzheimer’s disease [19]
[21]
[22]
[23]
[24]
[25]
[26]. Our objective was to compare the efficacy of Crocus sativus (stigma) with fluoxetine in treatment of mild to moderate postpartum depression in
a 6-week, double-blind, randomized clinical trial.
Method
Trial design
A 6-week, multicenter, randomized, double-blind, parallel-group clinical trial was
conducted in the outpatient clinics of Yas Women General Hospital, Arash and Baharloo
Hospitals (all affiliated with Tehran University of Medical Sciences, Tehran, Iran)
between September 2015 and December 2015.
The trial protocol was approved by the institutional review board (IRB) of Tehran
University of Medical Science (Grant No: 23220) and conducted consistent with the
Declaration of Helsinki and subsequent revisions. The trial was registered at the
Iranian registry of clinical trials (www.irct.ir; registration number: IRCT201509201556N82) prior to the study. Written informed consent
was obtained from all eligible participants and/or their legally authorized representatives.
Patients were informed that they were free to withdraw from the trial at any time
without any adverse effect on their relationship with their health care provider and
their therapy.
Participants
Women between 18–45 years of age, with a diagnosis of postpartum depression based
on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision (DSM-IV-TR) criteria were eligible to participate in the trial (4–12 weeks
after childbirth). Patients were required to have mild to moderate postpartum depression
at time of randomization, having a score≥10 and ≤18 in the 17-item Hamilton Depression
Rating Scale (HDRS) [27]
[28].
Exclusion criteria included: women with psychotic depression, history of suicidal
or infanticidal thoughts, a history of bipolar disorder, substance or alcohol dependence
(with the exception of nicotine dependence), lactation, hypothyroidism and acute medical
illness. Patients suffering from any diagnosis other than postpartum depression on
the DSM-IV-TR axis I were also excluded.
Interventions
Patients underwent a standard clinical assessment comprising a psychiatric evaluation,
a structured diagnostic interview and medical history. Eligible participants were
randomized to receive either a capsule of saffron (SaffroMood®, IMPIRAN, containing 15 mg of saffron extract) twice daily or a fluoxetine capsule
(Abidi, Iran, 20 mg capsule; each capsule had 1.65–1.75 mg crocin) twice daily for
6 weeks. Participants were not allowed to use any psychotropic drug or receive any
behavioral intervention therapy during the course of the trial.
Outcome
All participants were assessed using HDRS score at baseline and at weeks 1, 3 and
6. The HDRS contains 17 questions (on a 3-point or 5-point scale) that assess severity
of depressive symptoms. This scale has been applied in many clinical trials in Iran
exploring depression therapeutic efficacy [27]
[28]
[29]
[30]
[31]
[32]. The primary outcome measure of this trial was to evaluate efficacy of saffron compared
to fluoxetine in improving depressive symptoms in postpartum individuals using general
linear model repeated measures. The 2 groups were also compared regarding improvement
in HDRS scores from baseline HDRS score at each time point, partial responders (25–50%
reduction in the HDRS score), responders (≥50% reduction in HDRS score), remitters
(HDRS score≤7) and the time needed to respond to treatment. Response rate (≥50% decrease
in the HDRS score) and remission rate (HDRS score≤7) were compared between 2 groups.
In terms of adverse events, a 25-item checklist was provided to systematically record
the adverse events during the course of the trial. All participants were asked about
any adverse event that was not mentioned in the checklist. Participants were also
asked to immediately inform the research team about any unexpected symptom during
the study period.
Sample size estimation
Assuming a mean difference of 3 on the HDRS score between the saffron and the fluoxetine
groups, with a standard deviation (SD) of 3 on HDRS score, a power of 95% and a 2-tailed
significance level of 0.05, 27 patients were needed in each group. Moreover, after
assuming 25% attrition rate, 34 patients were needed in each group.
Randomization, allocation concealment and blinding
An independent party, who was not involved elsewhere in the trial, randomized codes
by permuted randomization block (blocks of 4, allocation ratio 1:1). Concealment of
allocation was performed using sequentially numbered, sealed opaque envelopes. An
aluminum foil inside the envelopes kept them impermeable to intense light. Study participant,
research investigator and the rater were all blind to the treatment allocation. Saffron
and fluoxetine capsules were indistinguishable in their shape, size, texture, color
and odor.
Statistical analyses
Frequency of categorical variables and mean±SD of continuous variables are reported.
General linear model repeated measure was used to compare HDRS scores between the
saffron and the fluoxetine groups. Whenever Mauchly’s test of sphericity was significant,
Greenhouse-Geisser adjustment was used for degrees of freedom. Independent t-test
was used to compare mean of continuous variables between treatment groups. Categorical
variables were compared using chi-square test and Fisher’s exact test where appropriate.
Statistical analysis was performed using Statistical Package of Social Science Software
(SPSS version 20, IBM Company, USA).
Results
Among 94 women who were screened for the eligibility criteria, 68 women were entered
into the trial and randomized to receive either saffron (n=34) or fluoxetine (n=34).
4 women were excluded from the trial due to their shift to moderate to severe depression,
and a total number of 64 patients (32 patients in each group) completed the trial
([Fig. 1]). Baseline characteristics of the study participants were not significantly different
between the treatment groups ([Table 1]).
Fig. 1 Flow diagram of the study.
Table 1 Baseline characteristics of the participants.
|
Variable
|
Saffron group (n=32)
|
Fluoxetine group (n=32)
|
P-value
|
|
Age, years, mean±SD
|
29.21±7.69
|
32.09±4.99
|
0.08
|
|
Smoking, n (%)
|
4 (12.5%)
|
3 (9.4%)
|
1.00
|
|
History of depression, n (%)
|
7 (21.9%)
|
9 (28.1%)
|
0.56
|
|
Working, n
|
26
|
24
|
1.00
|
|
Education
|
|
• Primary school
|
4
|
5
|
1.00
|
|
• High school diploma
|
26
|
24
|
|
• University degree
|
2
|
4
|
|
Baseline HDRS score, mean±SD
|
16.53±1.48
|
16.65±1.12
|
0.70
|
n=number; SD=standard deviation; HDRS=Hamilton Depression Rating Scale
Outcomes
HDRS score
Baseline HDRS scores were not significantly different between the saffron and the
fluoxetine groups (16.53±1.48 vs. 16.65±1.12, respectively, [MD (95% CI)=−0.12 (−0.78
to 0.53), t (57.84)=−0.38, p=0.70]). General linear model repeated measures demonstrated
insignificant effect for time×treatment interaction on HDRS score [F (4.90, 292.50)=1.04,
p=0.37] ([Fig. 2]). There was no significant difference between the 2 groups in terms of reduction
in HDRS score from baseline to each time, for partial responders, responders and remitters
([Table 2]). Remission rates were almost equal between 2 groups as [Table 2] shows 6 (18.8%) patients in the saffron group and 7 (21.9%) in the fluoxetine group
reached a HDRS≤7 by the end of this trial (p=1.00). 13 (40.60%) patients in the saffron
group experienced complete response (≥50% reduction in HDRS score) compared with 16
(50%) in the fluoxetine group, and the difference between the 2 groups was not significant
in this regard (p=0.61). Partial response rates were not significantly different between
the 2 groups as well; all 32 patients in the both group who completed the trial show≥25%
reduction in HDRS score by week 6 (p=1.00).
Fig. 2 Repeated measure for comparison of the effects of 2 treatments on Hamilton Depression
Rating Scale (HDRS). Values represent mean±standard deviations. P-values show the
result of the independent t-test for comparison of scores between the 2 groups at
each time interval. NS indicates non-significant.
Table 2 Comparison of score changes between the 2 groups and response to treatment.
|
HDRS score
|
Saffron group (Mean±SD)
|
Fluoxetine group (Mean±SD)
|
Mean difference Saffron – fluoxetine (95% CI)
|
P-value
|
|
Reduction from baseline to week 1
|
2.03±1.35
|
1.62±1.53
|
0.40 (−0.31 to −1.31)
|
0.27
|
|
Change from baseline to week 3
|
4.22±2.09
|
4.53±1.90
|
−0.31 (−1.31 to 0.68)
|
0.53
|
|
Change from baseline to week 6
|
7.50±1.97
|
7.71±1.69
|
−0.22 (−1.13 to 0.69)
|
0.63
|
|
Outcome
|
Saffron group (n=32)
|
Fluoxetine group (n=32)
|
Odds ratio
|
P-value
|
|
Number (%) of partial responders at week 3
|
15 (49.6%)
|
18 (56.2%)
|
0.68
|
0.61
|
|
Number (%) of partial responders at week 6
|
32 (100%)
|
32 (100%)
|
–
|
1.00
|
|
Number (%) of responders at week 3
|
2 (6.2%)
|
2 (6.2%)
|
1
|
1.00
|
|
Number (%) of responders at week 6
|
13 (40.60%)
|
16 (50%)
|
0.68
|
0.61
|
|
Number (%) of remitters at week 6
|
6 (18.8%)
|
7 (21.9%)
|
0.82
|
1.00
|
Side effects
The frequencies of adverse events observed during the trial are summarized in [Table 3]. Patients in the fluoxetine group experienced more headache, dry mouth, daytime
drowsiness, constipation and sweating than the saffron group. However, frequencies
of adverse events were not significantly different between the 2 groups. No major
adverse event and no death occurred.
Table 3 Frequency of adverse events in the 2 study groups.
|
Saffron (n=32)
|
Saffron (n=32)
|
Saffron (n=32)
|
Saffron (n=32)
|
|
Headache
|
1 (3.1%)
|
5 (15.6%)
|
0.19
|
|
Dry mouth
|
2 (6.2%)
|
4 (12.5%)
|
0.67
|
|
Nausea
|
4 (12.5%)
|
4 (12.5%)
|
1.00
|
|
Daytime drowsiness
|
1 (3.1%)
|
4 (12.5%)
|
0.35
|
|
Constipation
|
2 (6.2%)
|
4 (12.5%)
|
0.67
|
|
Sweating
|
1 (3.1%)
|
3 (9.4%)
|
0.61
|
Discussion
A postpartum depression takes a great toll on women and negatively affects social
interaction and infant development [3]. Mood control, especially the etiology of depressive disorders, is not completely
understood. However, substantial evidence has accumulated that serotonergic systems
play a central role [4]
[5]
[6]
[7]. Saffron is used as an antispasmodic, eupeptic, gingival, sedative, anticatarrhal,
nerve sedative, carminative, diaphoretic, expectorant, stimulant, stomachic, aphrodisiac
and antidepressant [18]. The search for new and more effective therapeutic agents includes the study of
plants used in traditional medicine to treat mental disorders [13]. Saffron is used for the treatment of depression in Persian traditional medicine
[22]. Corcin and safranal, 2 major components of saffron, inhibit reuptake of dopamine,
norepinephrine and serotonin [19]. This study was carried out to compare the antidepressant effect of saffron with
fluoxetine in mild to moderate postpartum depression. The results of this study emphasize
saffron is a safe alternative and as effective as fluoxetine in improving symptoms
of depression.
In this double-blind, randomized clinical trial, Crocus sativus was found to be effective almost like fluoxetine. Our findings are in line with recently
published studies that show Crocus sativus antidepressant effect [19]
[21]
[22]
[23]
[24]
[33]. A trial that compared the petal of Crocus sativus and fluoxetine in the treatment of depressed patients showed that the petal of Crocus sativus is as effective as fluoxetine [21]. Another clinical trial demonstrated that saffron is as effective as imipramine
in treatment of mild to moderate depression. Also, in the imipramine group, anticholinergic
effects such as dry mouth and sedation were observed more often as predicted [22]. A placebo-controlled trial showed that patients with mild to moderate depression
receiving saffron experienced statistically significant benefits in their mood after
6 weeks of treatment compared to placebo [23]. In another clinical trial, saffron was found to be effective in relieving symptoms
of PMS [24]. Shahmansouri et al. showed that short-term therapy with saffron capsules was associated
with the same antidepressant efficacy in comparison with fluoxetine in patients with
a prior history of post percutaneous coronary intervention who were suffering from
depression [33]. In our study, patients in the fluoxetine group experienced more headache, dry mouth,
daytime drowsiness, constipation and sweating than the saffron group. However, frequencies
of adverse events were not significantly different between the 2 groups. Limitations
of the present trial include lack of a placebo group, a small number of participants
and short period of follow-up. Since the trial is not well powered, large clinical
trials with longer treatment periods and comparison with placebo group would be appropriate
for future studies. It should be mentioned that the trial was the first study of saffron
in the treatment of postpartum depression. Therefore, we recruited only mild to moderate
depression and, as a result of this, the SD of severity score in the participants
was quite small. In addition, the findings of this study cannot be generalized to
severe depression. Nevertheless, the results of this study emphasize efficacy of saffron
in treatment of postpartum depression. On the other hand, the fewer side effects of
saffron compared with the classical antidepressant confirm application of saffron
as an alternative treatment of depression in traditional medicine.
Source of Funding
This study was supported by a grant from Tehran University of Medical Sciences (Grant
no: 23222) to Prof. Shahin Akhondzadeh. The funding organization had no role in the
design and conduct of the study; in the collection, analysis and interpretation of
the data; or in the preparation, review or approval of the manuscript and the decision
to submit the paper for publication. The current study complies with contemporary
laws and regulations in Iran.
