Key words
anxious distress - citalopram
Crocus sativus
- major depressive disorder
Introduction
Lifetime prevalence of major depression and anxiety disorders among adults in the
United States (US) has been reported to be 16.6 and 28.8 percent, respectively [1]. In a large-scale study, 75% of those with depression met the criteria for an anxiety
disorder and 79% of those with an anxiety disorder met the criteria for major depression
during their lifetime [2]. The terminology mixed anxiety-depressive disorder (MADD) in DSM-IV-TR did not reappear
in the appendix of DSM-5. Major depression, with anxious distress as a specifier,
is the term currently being used as an evidence-based terminology [3].
Patients with depression and concomitant anxiety appear to have increased functional
disability, significantly lower response and remission rates, longer illness duration,
greater likelihood of treatment nonresponse, greater disruption of social, work and
family life and a higher suicide risk compared to patients with non-anxious depression
[4]
[5]
[6]
[7]
[8]
[9]. As a result, it is clinically beneficial to specify the precise presence and severity
levels of anxious distress for treatment design and monitoring of the response to
treatment in patients with concomitant major depressive disorder (MDD) and anxious
distress [9].
Neurobiological evidence involving abnormalities of the serotonergic, noradrenergic,
glutamatergic, and γ-aminobutyric acidergic (GABAergic) transmission are indicated
to be involved in the pathophysiology of anxiety [10]. Hyperactivity within the amygdala is described to be one of the most consistent
abnormalities in the presence of anxiety and depression in one person, which is shown
to be in response to hyperactivity in the locus coeruleus [11]
[12]. It cannot be concluded that the amygdala causes anxious depression, because depression
and anxiety with neurotransmitter changes might cause alterations in the amygdala.
The ideal treatment for depression and anxiety should take the form of a single drug
that is efficacious in the treatment of both disorders [13]. Treatment of depression and anxiety is not easily achieved with a single medication
[14] because anxiety symptoms might occur during the anti-depressant treatment, although
this side effect usually occurs only in the initial days of treatment and is commonly
treated with benzodiazepine administration. In some cases where benzodiazepines are
not indicated, quetiapine, olanzapine, an olanzapine-fluoxetine combination, pregabalin,
and silexan could be assumed to have positive effects [15]. Safety in overdose is also important as there is a higher risk of suicide in patients
with MDD with associated anxiety than in those with depression alone [16]. Selective serotonin reuptake inhibitors (SSRIs) are accepted as first-line treatment
for this group of patients [17]. During SSRI therapy, the most troubling adverse effects are sexual dysfunction,
gastrointestinal disturbances, weight gain, anxiety, agitation, and sleep disturbances
[18]
[19]
[20]. Overall, citalopram appears to be the best-tolerated SSRI [21]. Agomelatine is also indicated to be efficacious in treating anxiety in major depression
with few side effects, although more long-term studies seem to be needed to justify
this medication [22]. Anticipated side effects of synthetic antidepressants decrease treatment compliance
in many patients, resulting in inadequate response to the treatment course [18]. For this group of patients, switching medications, a combination therapy with benzodiazepines,
psychological therapy or trying alternative herbal medicinal approaches seem to be
reasonable steps [23]. Many effective herbal drugs, presented as “over-the-counter” psychotropics, offer
advantages in terms of safety and present fewer side effects with better tolerability
in comparison to conventional pharmacotherapies. A combination of imipramine and lavandula
tincture has shown to be more effective than imipramine alone; saffron is indicated
to have the same antidepressant efficacy compared to fluoxetine in patients with a
prior history of PCI; short-term therapy with saffron capsules may safely and effectively
improve some of the fluoxetine-induced sexual problems including arousal, lubrication,
and pain [24]
[25]
[26]. Silexan (lavender) is another herbal medicine indicated to be efficacious and safe
in the treatment of MADD [27]. Collected data of patients suffering from anxiety and depression shows that large
numbers of patients, in some cases more than 50%, reported using herbal, complementary
and alternative medicine to treat their symptoms during the previous 12 months [28]
[29]. Because not all frequently used phytomedicines are safe, targeting the safe and
optimal dose of the employed herbal medicines should be considered carefully.
Targeting multiple neuroendocrine systems in comparison to a single neurotransmitter
might be a more successful approach due to the complexity of the psychiatric disorders.
In addition, various research suggests that the presence of different psychoactive
compounds in a plant might have a synergistic effect, and that the biological effects
of plants might rely on synergistic and polyvalent interactions between their components
[30]. The mechanism of action of medicinal plants involves both central nervous system
(CNS) activity and endocrine system functionality [31]
[32], which may potentially impact the treatment of comorbid psychiatric disorders (e. g.,
if depression is treated, then anxiety may also resolve) [33].
Crocus sativus L., commonly known as saffron, is an herb cultivated in various parts of the world
such as Iran, China, Spain, India and Greece. In traditional folk medicine, saffron
is recommended as an aphrodisiac, antispasmodic, eupeptic, digestive, anticatarrhal,
expectorant, antiseptic, antidepressant, anticancer and anticonvulsant [34]
[35]. Crocus sativus has been approved for use in major depression by the Canadian Network for Mood and
Anxiety Treatments [36]. Suggested saffron mechanisms of action are as follows: increase in re-uptake inhibition
of monoamines (dopamine, norepinephrine, and serotonin), N-methyl-D-aspartic acid
(NMDA) receptor antagonism, and GABA-α agonism [32]. Saffron and its active constituents that act on different CNS processes have been
widely studied and various benefits have been scientifically proven, including antidepressant
[37], anti-anxiety [38], neuroprotective in a rat model of Parkinson’s disease [39], antagonizing memory impairments in rodents [40]
[41], and enhancing spatial cognitive abilities after chronic cerebral hypoperfusion
[42]
[43]. Spice supplementation with saffron is revealed to be effective for improving depressive
symptoms in non-clinically depressed populations [44]. In clinical studies, saffron not only had significantly greater antidepressant
properties compared with placebo [45]
[46], but it also was shown to be as efficient as conventional antidepressants such as
imipramine and fluoxetine [47]
[48]
[49]. In addition, saffron has demonstrated extensive anxiolytic effects in experimental
models [42]
[50]
[51].
We hypothesized that saffron would show satisfactory outcomes in treatment of MDD
with concomitant anxiety distress. Thus, our main objective was to compare the tolerability,
safety and efficacy of Crocus sativus to citalopram in the treatment of MDD with anxious distress using a double-blind,
randomized controlled trial design.
Methods
Trial design and setting
The study was conducted as a multicenter, prospective, 6-week, parallel-group, double-blind,
randomized clinical trial at the outpatient clinic of Baharloo hospital (Tehran University
of Medical Sciences, Tehran, Iran) and Farshchian Hospital (Hamadan University of
Medical Sciences, Hamadan, Iran) from January 2015 to April 2016. The trial protocol
was registered at the Iranian registry of clinical trials (www.irct.ir; trial identifier with the IRCT database: IRCT201501041556N71) and was approved by
the institutional review board (IRB) of the Tehran University of Medical Sciences
protocol (Grant No. 27225).
Participants
Eligible patients were men and women aged 18–65 years with a diagnosis of mild to
moderate major depression with anxious distress according to the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition, (DSM-5), with a score<19 on the 17-item
Hamilton Rating Scale for Depression (HAM-D) for mild to moderate depression and a
score<24 in the 14-item Hamilton Rating Scale for Anxiety (HAM-A) to be of mild to
moderate severity. Participants were recruited during routine visits of psychiatric
clinics. Based on the inclusion criteria, patients were fully informed about the project.
Assessment of patients was on a routine 2-week-interval visit based on a questionnaire
derivative of the HAM-D and HAM-A rating scales. 2 experienced and senior psychiatrists
rated the patients in psychiatric outpatient clinics.
Exclusion criteria
Receipt of any antidepressant medication during the previous month; receipt of electroconvulsive
therapy (ECT) during the last 2 months; diagnosis of other mental disorders on the
DSM-IV Axis I; alcohol or substance (with the exception of nicotine) dependence; severe
depression or suicidal ideation (those who were judged to have substantial risk for
suicide by the physician or scored >2 on the suicide item of the HDRS); receipt of
aspirin, anticoagulants or NSAIDs (Persian traditional medicine asserts that saffron
at high dosages can induce abnormal bleeding); and any uncontrolled medical problem
such as hypertension, hypothyroidism, or renal failure. Women who were nursing, pregnant,
lactating, receiving OCP, or wanted to become pregnant in the near future were also
excluded. In addition, any clinically significant deterioration in the condition of
the subject from baseline would result in exclusion from the trial. The study was
conducted in accordance with the established tenets of the Declaration of Helsinki
and its subsequent revisions. After a complete description of the study details, the
patients and their legally authorized representative provided informed consent in
accordance with the procedures. The participants were informed that withdrawal from
the study, at any time, was allowed without compromising their relationship with their
health care provider.
Interventions
Eligible patients randomly received either citalopram (citalopram, Sobhan Darou, 20 mg
capsules) or saffron (SaffroMood, IMPIRAN, containing 15 mg of saffron extract) in
the same manner for 6 weeks. Following the selection phase, a capsule of saffron (15 mg)
or a capsule of citalopram (20 mg) was given for the first week, after which the dose
was increased to 2 capsules of saffron or citalopram per day for the rest of the trial.
Therefore, the prominent dose of citalopram and saffron was 40 mg/day and 30 mg/day,
respectively. Participants were not allowed to use any other psychotropic medication
or undergo behavioral intervention therapy during the trial course. Medication adherence
was measured using weekly capsule counts justified against participant reports of
medication intake to calculate the proportion of dispensed medication doses that were
actually ingested. Preparation of Crocus sativus stigma extract is described in detail in the Modabbernia et al. study [52]. The stigma extract was standardized based on crocin by means of spectrophotometry.
The crocin value is expressed as a direct reading of the absorbance at about 440 nm.
Each capsule had 1.65–1.75 mg crocin.
Primary and secondary outcome measures
Participants were evaluated using HAM-D and HAM-A at baseline and at weeks 2, 4 and
6 post-intervention. HAM-D is a validated 17-item rating scale that has been widely
applied in psychiatric studies to measure the severity of depressive symptoms and
also has been used to evaluate treatment efficacy and severity of depressive symptoms
in several clinical trials in Iran [53]
[54]
[55]
[56]
[57]. HAM-A is a 14-parameter rating scale to assess the patient’s response to a course
of treatment, and by administering the scale serially, results of drug treatment or
psychotherapy could be documented. The primary outcome measure was to evaluate the
efficacy of saffron in improving depressive and anxiety symptoms compared with citalopram
during the trial course using a general, linear, repeated-measures model. The secondary
outcome measures of this trial were comparison of changes in the HAM-D and the HAM-A
score from baseline to each time point, response to treatment (defined as ≥50% reduction
in the HAM-D score) and remission (defined as HAM-D score≤7) rates between the treatment
groups, and evaluation of the antidepressant effects of saffron specifically. Treatment
failure was defined as persistence of clinical signs and symptoms. Adverse events
were systematically evaluated at each time point using a checklist. Furthermore, patients
were first asked an open-ended question about any adverse event that was not mentioned
on the checklist. Patients were also asked to immediately inform the research team
of any unexpected symptom during the trial course. Electrocardiography was performed
if patients complained of any typical or atypical cardiac syndromes. 2 experienced
and senior psychiatrists rated the patients. We used the kappa correlation method
to calculate inter-rater reliability. Interviews of raters with 6 random patients
diagnosed with MDD and anxious distress resulted in >90% inter-rater reliability.
Sample size determination
A minimal sample size of 58 (29 patients in each group) was calculated assuming a
clinically significant difference of 3 on the HAM-D score, an SD of 4 (based on our
pilot study), a two-sided significance level of 0.05, and a power of 80%. A final
sample size of 65 was planned, assuming an attrition rate of 10%. To achieve a perfect
score ratio of 1.0 for the saffron and citalopram allocation groups, the required
sample size was calculated at 66 patients (33 patients in each group).
Protocol of randomization and drug allocation
An independent group that was not involved elsewhere in the study was in charge of
generation of randomization codes, using a computerized random number generator (blocks
of 4, allocation ratio 1:1). Concealment of allocation was performed through sequentially
numbered and sealed opaque and stapled packages. Separate people were responsible
for random allocation and rating of patients. Citalopram and saffron capsules were
visually identical in terms of shape, odor, and color. The participants, the physician
who referred the patients, the physician who prescribed the medications, the investigators
who rated the participants and the statistician were all blinded to the treatment
group assignment.
Statistical methods
Statistical analysis was conducted using the Statistical Package for the Social Sciences
(SPSS Version 20.0 IBM Corporation, Armonk, NY, USA). All analyses were performed
based on the intention-to-treat principles with 3 post-baseline measurements. Categorical
variables and continuous variables were reported as frequency (percentage) and mean±SD,
respectively. Baseline continuous variables were compared using the independent t-test.
The mean difference (MD) between the saffron and the citalopram group was reported
as MD (95% CI). A two-factor repeated-measures analysis of variance (ANOVA) was used
to evaluate time×treatment interaction. Results of Greenhouse-Geisser adjustment were
reported if Mauchly’s test of sphericity was significant. The independent t-test and
Cohen’s d effect size were used to compare score changes from baseline to each time
interval between the 2 study groups. To compare HAM-D and HAM-A scores at baseline
with each time point in each group, the paired t-test was used. Categorical variables
were compared using the χ2 test or Fisher’s exact test. The Kaplan-Meier estimation with log-rank test was used
for comparison of the time needed to partially respond to treatment between groups.
P-values<0.05 were considered the bare minimum to flag statistically significant correlations.
Results
A total of 94 patients were screened for eligibility: 66 patients were randomly assigned
to receive either saffron (n=33) or citalopram (n=33), but only 60 patients (divided
into 2 equal groups of 30 for each arm) completed the trial program and remained compliant
with their treatment during the running study period. Those 60 had 2 post-baseline
measurements at weeks 2, 4 and 6 of the follow-up period ([Fig. 1]). The 6 patients who discontinued the study withdrew consent for personal reasons
before the first evaluation in week 2. As summarized in [Table 1], baseline recorded data were comparable between the saffron and the citalopram treatment
arms.
Fig. 1 Flow diagram representing case selection for the trial program.
Table 1 Baseline characteristics of study population.
|
Item
|
Citalopram Arm (n=30)
|
Saffron Arm (n=30)
|
P-value
|
|
Age (y)
|
34.17±10.41
|
37.90±11.56
|
0.194
|
|
Sex, Male (%)
|
15 (50)
|
11 (36.7)
|
0.297
|
|
Marital Status, n (%)
|
0.312α
|
|
Married
|
23 (76.7)
|
19 (63.3)
|
|
Single
|
6 (20)
|
10 (33.3)
|
|
Widow/Widower
|
0
|
1 (3.3)
|
|
Divorcee
|
1 (3.3)
|
0
|
|
Educational Status, n (%)
|
0.376α
|
|
Illiterate
|
1 (3.3)
|
4 (13.3)
|
|
Primary School
|
8 (26.7)
|
7 (23.3)
|
|
Secondary School
|
5 (16.7)
|
9 (30)
|
|
Diploma
|
9 (30)
|
6 (20)
|
|
University Degree
|
7 (23.3)
|
4 (13.3)
|
|
Occupation
|
0.210α
|
|
Unemployed
|
0
|
3 (10)
|
|
Worker
|
3 (10)
|
6 (20)
|
|
Clerk
|
5 (16.7)
|
2 (6.7)
|
|
Student
|
6 (20)
|
2 (6.7)
|
|
Housewife
|
13 (43.3)
|
14 (46.7)
|
|
Other
|
3 (10)
|
3 (10)
|
|
Duration of Illness, months, mean±SD
|
3.33±1.35
|
3.93±1.64
|
0.127
|
|
Addiction, n (%)
|
0.353α
|
|
Yes
|
1 (3.3)
|
4 (13.3)
|
|
No
|
29 (96.7)
|
26 (86.7)
|
|
Baseline HAM-A Score
|
19.10±2.60
|
19.67±4.40
|
0.547
|
|
Baseline HAM-D Score
|
17.50±0.63
|
17.20±1.40
|
0.289
|
HAM-A, Hamilton Rating Scale for Anxiety; HAM-D, Hamilton Rating Scale for Depression
α P-value reported by Fisher’s exact test
HAM-A score
Baseline HAM-A scores were not significantly different between the citalopram and
the saffron intervention groups: mean citalopram-saffron difference (MD) (95%CI)=−0.57
(−2.45 to 1.31); t (58)=−0.607; P-value=0.547 ([Table 1]). Two-factor repeated-measures ANOVA demonstrated that the effect of time×intervention
interaction term on reducing the HAM-D scores was not statistically significant during
the follow-up period: F (2.49, 144.41)=0.005; p=0.999 ([Fig. 2]). In line with this observation, improvements made in the HAM-A score were not significantly
different at week 2, 4 or 6 post-intervention between the treatment groups ([Fig. 2] and [Table 2]). However, there were significant improvements in the HAM-A score at weeks 2, 4
and 6 for both the citalopram and the saffron treatment groups ([Table 3]).
Fig. 2 Comparison of mean ± SD of Hamilton Rating Scale for Anxiety scores at baseline and
post-intervention with citalopram or saffron over time. (NS denotes the nonsignificant
difference in the Hamilton Rating Scale for Anxiety scores between the trial arms
at each measurement).
Table 2 Comparison of score changes between the 2 trial arms using the Independent t-test.
|
Outcome
|
Citalopram Arm (n=30)
|
Saffron Arm (n=30)
|
Mean Difference: Citalopram-Saffron (95% CI)
|
Cohen’s d
|
P-Value
|
|
HAM-A Score
|
|
Change from baseline to week 2, mean±SD
|
2.60±4.98
|
2.50±4.49
|
0.10 (−2.35 to 2.55)
|
0.02
|
0.935
|
|
Change from baseline to week 4, mean±SD
|
7.47±5.22
|
7.53±5.56
|
−0.07 (−2.86 to 2.72)
|
−0.01
|
0.962
|
|
Change from baseline to week 6, mean±SD
|
12.07±6.03
|
12.03±7.02
|
0.03 (−3.35 to 3.42)
|
0.01
|
0.984
|
|
HAM-D Score
|
|
Change from baseline to week 2, mean±SD
|
2.17±2.63
|
1.83±3.70
|
0.33 (−1.33 to 2.00)
|
0.11
|
0.689
|
|
Change from baseline to week 4, mean±SD
|
5.97±3.42
|
5.07±5.11
|
0.90 (−1.35 to 3.15)
|
0.21
|
0.427
|
|
Change from baseline to week 6, mean±SD
|
11.27±3.67
|
10.13±5.96
|
1.13 (−1.44 to 3.70)
|
0.23
|
0.380
|
Abbreviations are given at [Table 1]
Table 3 Comparison of the scores at each time point with the baseline values in each trial
arm using the paired t-test.
|
Outcome
|
Score at Week 2, Mean±SD
|
P-Value
|
Score at Week 4, Mean±SD
|
P-Value
|
Score at Week 6, Mean±SD
|
P-Value
|
|
HAM-A Score
|
|
Citalopram Arm (n=30)
|
16.50±4.46
|
0.008
|
11.63±4.75
|
<0.001
|
7.03±4.96
|
<0.001
|
|
Saffron Arm (n=30)
|
17.17±6.30
|
0.005
|
12.13±6.37
|
<0.001
|
7.63±6.52
|
<0.001
|
|
HAM-D Score
|
|
Citalopram Arm (n=30)
|
15.33±2.51
|
<0.001
|
11.53±3.22
|
<0.001
|
6.23±3.59
|
<0.001
|
|
Saffron Arm (n=30)
|
15.37±3.81
|
0.011
|
12.13±5.01
|
<0.001
|
7.07±5.84
|
<0.001
|
Abbreviations are given at [Table 1]
HAM-D score
A two-factor generalized linear model repeated measures on the HAM-D score (effect:
time×treatment interaction term) did not demonstrate a significant reducing effect
on the severity of depressive symptoms (F
2.42, 140.66=0.393, P-value=0.715, [Fig. 3]). Similar to the HAM-A score, there were no statistically significant differences
in baseline HAM-D scores between the citalopram and the saffron arms [17.50±0.63 vs.
17.20±1.40; respectively, MD for citalopram-saffron (95% CI)=0.30 (−0.26 to 0.86),
t (58)=1.07, P-value=0.289]. Reductions in HAM-D scores were comparable across the citalopram and
saffron intervention arms by week 2 (2.17±2.63 vs. 1.83±3.70, p=0.689), week 4 (5.97±3.42 vs. 5.07±5.11, p=0.689) and week 6 (11.27±3.67 vs. 10.13±5.96, p=0.380) of the follow-up period ([Table 2]). Moreover, score reductions for the HAM-D score were significant for both groups
of individuals receiving citalopram and saffron at each post-baseline checkpoint at
week 2, 4 and 6 ([Table 3]).
Fig. 3 Comparison of mean ± SD of Hamilton Rating Scale for Depression scores at baseline
and post-intervention with citalopram or saffron over time. (NS denotes the nonsignificant
difference in the Hamilton Rating Scale for Depression scores between the trial arms
at each measurement).
Treatment response and remission rates
As [Table 4] demonstrates, the number of responses (≥50% reduction in the HAM-D score) and remissions
(HAM-D≤7) at weeks 2, 4 and 6 post-intervention were not statistically different among
individuals receiving either citalopram or saffron ([Table 4]). However, the remission rate was not far from being significant after 6 weeks (P-value=0.072).
Average (±SD) time to response and time to remission intervals in the entire study
population were 5.23±0.17 and 5.57±0.13, respectively. Using Kaplan-Meier estimate
curves, we observed participants in the saffron arm display comparable time-to-response
periods compared with those consuming citalopram (mean±SD time to response: 5.07±0.25
vs. 5.40±0.22 weeks, respectively; log-rank p=0.706). Moreover, patients who were
on saffron or citalopram also achieved similar average times to remission (5.40±0.22
vs. 5.73±0.13; log-rank p=0.306).
Table 4 Comparison of response to treatment and remission rates at different study points
between the 2 trial arms.
|
Outcome
|
Citalopram Arm (n=20)
|
Saffron Arm (n=20)
|
P-valueα
|
Odds ratio
|
|
HAM-D
|
|
Number (%) of responders, at week 2
|
1 (3.3)
|
3 (10)
|
0.612α
|
0.64
|
|
Number (%) of responders, at week 4
|
7 (23.3)
|
11 (36.7)
|
0.260
|
0.74
|
|
Number (%) of responders, at week 6
|
27 (90)
|
22 (73.3)
|
0.181α
|
1.62
|
|
Number (%) of remissions, at week 2
|
0
|
2 (6.7)
|
0.492
|
n/a
|
|
Number (%) of remissions, at week 4
|
4 (13.3)
|
7 (23.3)
|
0.506
|
0.738
|
|
Number (%) of remissions, at week 6
|
26 (86.7)
|
19 (63.3)
|
0.072α
|
1.737
|
α reported by Fisher’s exact test. n/a: not applicable
Adverse events
Aside from vertigo that seemed to occur more frequently in the citalopram arm (although
was not statistically significant), frequencies of other observed adverse outcomes
were comparable across the intervention groups ([Table 5]). No symptoms of adverse cardiovascular events occurred in the study population,
which was confirmed by physical examination and normal ECG recordings. No serious
adverse events or deaths were observed. Vertigo and anger/rage were the most commonly
observed adverse symptoms in the citalopram arm. By comparison, headache and nausea/vomiting
were the only adverse outcomes affecting the individuals receiving saffron, each affecting
2 of the patients. No treatment discontinuation was observed as a result of drug adverse
events. Symptoms had begun to decrease by the third week and were sustained until
study completion ([Table 5]).
Table 5 Frequency [n (%)] of unwanted side effects among the 2 trial arms.
|
Side effect
|
Citalopram Arm (n=30)
|
Saffron Arm (n=30)
|
P-Valueα
|
|
Headache
|
2 (6.7)
|
2 (6.7)
|
1.000
|
|
Vertigo
|
5 (16.7)
|
0
|
0.052
|
|
Nausea/Vomiting
|
2 (6.7)
|
2 (6.7)
|
1.000
|
|
Drowsiness
|
2 (6.7)
|
0
|
0.492
|
|
Gastritis
|
2 (6.7)
|
0
|
0.492
|
|
Anger/Rage
|
3 (10.0)
|
0
|
0.237
|
|
Palpitation
|
1 (3.3)
|
0
|
1.000
|
α reported by Fisher’s exact test
Abbreviations are given at [Table 1]
Discussion
The present study provides evidence for satisfactory outcomes with saffron in the
treatment of mild to moderate MDD with anxious distress (15 mg, 2 capsules per day).
In this double-blind and randomized clinical study of Crocus sativus stigma vs. citalopram in the treatment of mild to moderate depression with concomitant
anxiety, Crocus sativus was demonstrated to be as safe and effective as citalopram for up to 6 weeks after
treatment initiation. The clinical relevance of this finding was emphasized by the
improvements seen in HAM-D and HAM-A measures in both groups. The response rate (≥50%
reduction in the HAM-D score) and remission rate (HAM-D≤7) were not significantly
different between patients receiving either saffron or citalopram, and although the
comparison of remission rates after 6 weeks (P-value=0.072) might be of interest,
it might never be significant. These findings are especially noteworthy because the
baseline characteristics of patients were comparable across the 2 trial arms.
After decades of predominant reliance on synthetic antidepressants, complementary
psychopharmacology research is becoming an area of interest due to safety concerns
and side effects of conventional antidepressant treatments. Phytomedicines are becoming
increasingly popular as alternatives to approved medications [33]. Better cultural acceptability and largely better profiles of side effects has made
complementary medicine the backbone of therapy predominantly in primary health care
of developing countries and for approximately 75–80% of the world population. Recently,
developed nations have also experienced a major growth in complementary medicine use
[58].
To the best of our knowledge, the current study is the first clinical trial of saffron
in treatment of MDD with anxious distress. Results of previous clinical trials showed
that saffron is more effective than placebo therapy [45]
[46] and can be compared with fluoxetine [48] and imipramine [49] in the treatment of major depression at the same dose used in the current study.
Fluoxetine is as effective as either petal [47] or stigma [48] of saffron. At present, it is not possible to draw valid comparisons with results
from other trials in the field of anxiety although animal studies have shown significant
saffron effects as an anxiolytic agent [42].
Our results show the same efficacy in treatment with citalopram (40 mg/day) or saffron
(30 mg/day). It can be conjectured that higher doses of saffron might exert even greater
beneficial effects, as higher doses of saffron showed greater results in 2 articles
on sexual function [52]
[59]. At this point, we recommend further clinical trials with higher doses of saffron
and greater trial duration to evaluate the effect of higher doses in patients with
MDD with anxious distress. The mechanism of action of saffron is not entirely known.
According to previous studies, anti-inflammatory, antioxidant, HPA-modulating, neuroprotective
effects, reuptake inhibition of monoamines, NMDA antagonism, improved brain-derived
neurotrophic factor signaling, and serotonin reuptake inhibition in synapses may be
among the main mechanistic factors [60]
[61]
[62]
[63].
In terms of safety, no significant difference was detected between the 2 trial arms
in the frequency of adverse events. In a review of clinical trials on saffron, no
severe adverse events were reported associated with the use of saffron supplementation.
The Jadad score for all the trials included in the review was 5, indicating high-quality
trials. Headache, nausea, anxiety, and decreased appetite were the most frequently
reported adverse effects [61]. Compared with synthetic antidepressants, the long-term safety profile of saffron
seems positive, although this requires further investigation. Long-term studies of
saffron have indicated few adverse effects at 22 weeks and up to 1 year after initiation
of the therapy [64]
[65]. A small number of adverse effects have been reported after high dose administration
of saffron in laboratory settings, but to the best of our knowledge, no serious adverse
event has been observed to date in well-designed clinical trials investigating therapeutic
doses of saffron in various disorders [51]
[66]
[67]. In an animal study, LD50 values of saffron stigma and petal extracts were 1.6 g/kg
and 6 g/kg, respectively [66], which is much higher than routine daily or therapeutic doses, indicating no serious
concern regarding overdose by saffron therapy. Regarding the cardiovascular system,
saffron is not only safe but also has some valuable cardioprotective properties such
as improving lipid profiles, decreasing blood pressure, and inhibiting atherosclerotic
plaque formation [68]. Drawing a firm conclusion about using saffron as a first-line treatment in MDD
with anxious distress is not possible yet largely due to a lack of precise data on
the mechanism of action of saffron. Endurable side effects of saffron may well confirm
the application of saffron as an alternative medication in Persian traditional medicine,
which justifies its importance as a drug of the future.
Limitations
Even though the present study has several advantages such as the multicenter, double-blind,
randomized design and the rigorous adjustment for baseline clinical variables, various
limitations should be addressed to prevent over-generalization of the findings. Although
the superiority of saffron in relation to placebo for treatment of depression has
been well documented [45]
[46], the lack of a placebo control trial arm and the use of only a fixed dose of saffron
therapy are considered as being among the main limitations. The study population size
was relatively small and the short follow-up period should also be considered.
Conclusion
The current study indicates that during a 6-week trial period, administration of saffron
is as safe and as effective as citalopram in the treatment of MDD with anxious distress.
It might be time to look more seriously at this valuable herbal medication. This observation
suggests saffron as a possibly useful strategy for monotherapy or as part of alternative
management in patients with MDD and concomitant anxious distress.
Source of Funding
This study was supported by a grant from Tehran University of Medical Sciences (Grant
No: 27225).
