JAMDA xxx (2017) 1e6

JAMDA
journal homepage: www.jamda.com

Original Study

Clinical Use of Curcumin in Depression: A Meta-Analysis

Qin Xiang Nga, *, Shawn Shao Hong Kohb, Hwei Wuen Chan MBBS, MMed c,
Collin Yih Xian Ho MBBS c
a
Yong Loo Lin School of Medicine, National University of Singapore, Singapore
b
Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
c
National University Hospital, National University Health System, Singapore

a b s t r a c t

Keywords: Introduction: There is growing interest in the use of curcumin, a plant polyphenol with potent anti-
Depression inflammatory, anti-oxidant, and neuroprotective properties, as a novel antidepressant. Clinical trials
complementary and alternative medicine have yielded conflicting conclusions pertaining to its effectiveness in depression. A meta-analysis of the
curcumin
topic, which has not been done until now, is therefore necessary to summarize current evidence and
curcuminoid
generate hypotheses for further research.
antidepressant
neuroprotective Methods: Using the keywords [curcumin OR diferuloylmethane OR curcuminoid OR turmeric OR Indian
saffron] AND [depression OR MDD OR suicide], a preliminary search on the PubMed, Ovid, Clinical Trials
Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR), and
Cochrane Field for Complementary Medicine database yielded 2081 articles published in English be-
tween January 1, 1960, and August 1, 2016.
Results: Six clinical trials with a total of 377 patients were reviewed, comparing the use of curcumin to
placebo. In patients with depression, the pooled standardized mean difference from baseline Hamilton
Rating Scale for Depression scores (pooled standardized mean difference
0.344, 95% confidence in-
terval
0.558 to
0.129; P ¼ .002) support the significant clinical efficacy of curcumin in ameliorating
depressive symptoms. Significant anti-anxiety effects were also reported in 3 of the trials. Notably, no
adverse events were reported in any of the trials. Most trials had a generally low risk of bias, except for an
open trial of curcumin and a single-blinded study.
Limitations: Because of the small number of studies available, a funnel plot or sensitivity analysis was not
possible. Evidence on the long-term efficacy and safety of curcumin is also limited as the duration of all
available studies ranged from 4 to 8 weeks.
Conclusions: Curcumin appears to be safe, well-tolerated, and efficacious among depressed patients.
More robust randomized controlled trials with larger sample sizes and follow-up studies carried out over
a longer duration should be planned to ascertain its benefits.
Ó 2016 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

According to the World Health Organization, depression is a highly
prevalent and debilitating mental disorder affecting more than 350
million people worldwide.1 It is the leading cause of disability and a
major contributor to the overall global burden of disease.2 Depression
is common in patients living with chronic diseases, and patients with
depression are also at increased risk of suicide and have higher rates of
medical and psychiatric comorbidities.3 Furthermore, approximately
The authors declare no conflicts of interest.
* Address correspondence to Qin Xiang Ng, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore 117597, Singapore.
E-mail address: ng.qin.xiang@u.nus.edu (Q.X. Ng).
one-half of patients with major depressive disorder fail to respond to
first-line treatment, and initial response to standard first-line medi-
cations such as selective serotonin reuptake inhibitors (SSRIs) may
take as long as 4 to 6 weeks.4e6 Even with successful treatment of
depression, there is often only partial remission of symptoms.7 There
is a pressing need to research newer and more effective treatments for
major depressive disorder.
Traditional medicine is often a fertile ground for new drug candi-
dates and the development of modern medicines.8 Curcumin (difer-
uloylmethane) is a bright yellow plant pigment, and the principal
curcuminoid present in Indian saffron or turmeric (Curcuma longa), a
popular spice and food additive widely used in South Asian and
Middle Eastern countries.9 Curcumin is also used in Ayurvedic

http://dx.doi.org/10.1016/j.jamda.2016.12.071
1525-8610/Ó 2016 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
2 Q.X. Ng et al. / JAMDA xxx (2017) 1e6

medicine to treat various inflammatory conditions (eg, arthritis and Because of the small number of studies available, publication bias
ulcers).10 Curcumin is also an important active ingredient found in the was not assessed using a funnel plot or Egger test, and a sensitivity
traditional Chinese medicine Jieyu-wan and Xiaoyao-san, which have analysis was not done. All analyses were done using MedCalc Statis-
been used for centuries to manage stress, depression, and other mood tical Software v 14.8.1 (MedCalc Software bvba, Ostend, Belgium;
disorders.11 http://www.medcalc.org; 2014).
Previous studies have reported the potent anti-oxidant,12 anti-in-
flammatory,13 and neuroprotective14 effects of curcumin. Many pre-
Results
clinical trials have also highlighted curcumin’s potential
antidepressant-like effects in rat15 and mice11 models of depression,
A total of 2081 records were identified through PubMed, Ovid,
with similar effects to conventional antidepressants like fluoxetine
Clinical Trials Register of the Cochrane Collaboration Depression,
and imipramine.16 These results are promising for they support the
Anxiety and Neurosis Group (CCDANTR), and Cochrane Field for
possible use of curcumin to treat depressive disorders. Clinical trials
Complementary Medicine database search. Of these, 11 full text arti-
have also been conducted but have yielded conflicting conclusions
cles were reviewed and considered for inclusion. The abstraction
pertaining to the effectiveness of curcumin in major depressive dis-
process and the reason(s) for exclusion of each study after full-text
order.17e19 A meta-analysis of the topic, which has not been done until
review were detailed in Figure 1. Altogether, 6 studies were
now, is, thus, timely and necessary to summarize current evidence and
included in the meta-analysis. The key study characteristics and
generate hypotheses for further research.
findings were summarized in Table 1.
The studies were assessed using the Cochrane Collaboration’s tool
Methods
for bias. The results were detailed in Table 2. Most studies had a low
risk of bias, except for an open trial of curcumin,24 which did not blind
Patient Involvement
the assessors or patients about the treatment received. Another
study25 was only single-blinded.
This article does not contain any studies with human partici-
Because of the small number of studies available, a funnel plot or
pants performed by any of the authors. Patients/service users/
sensitivity analysis was not feasible.
carers/lay people were not involved in the design or course of this
The pooled SMD from baseline HAM-D scores (pooled SMD
0.344,
study.
95% CI
0.558 to
0.129; P ¼ .002) supports the clinical efficacy of
curcumin in ameliorating depressive symptoms when compared with
Search Strategy
placebo/control. This was illustrated in a forest plot (Figure 2).
Insufficient outcome data were available to analyse the risk or odds
Literature search was done in accordance with Preferred Reporting
ratio of adverse events related to curcumin use. It is, however,
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
encouraging that no adverse events were reported in any of the trials.
Using the keywords [curcumin OR diferuloylmethane OR curcuminoid
OR turmeric OR Indian saffron] AND [depression OR MDD OR suicide],
a preliminary search on the PubMed, Ovid, Clinical Trials Register of Discussion
the Cochrane Collaboration Depression, Anxiety and Neurosis Group
(CCDANTR), and Cochrane Field for Complementary Medicine data- The available clinical trials generally support the antidepressant
base yielded 2081 articles published in English between January 1, effects of curcumin administration in depressed patients. The pooled
1960, and August 1, 2016. Gray literature was not searched. Title/ab- SMD from baseline HAM-D scores (pooled SMD
0.344, 95% CI
0.558
stract screening were performed independently by the researchers to
identify articles of interest. For relevant abstracts, full articles were
obtained, reviewed, and also checked for references of interest. The
authors of the articles were not contacted to provide additional data.
Full articles were obtained for all selected abstracts and reviewed by
all researchers for inclusion. Any disagreement was resolved by discus-
sion and consensus among the 3 researchers. The inclusion criteria for
this review were (1) published randomized controlled trial; (2) specified
dose of curcumin was administered as an active intervention; (3) study
participants had clinically diagnosed major depressive disorder; and (4)
available outcome measures for treatment efficacy and safety.
Methodological quality of the eligible clinical trials was appraised
using the Jadad scale20 by all investigators (consensus). Trials were
scored between 0 (very poor) and 5 (rigorous). Cochrane Collabora-
tion’s tool for assessing risk of bias21 of randomized controlled trials
was also applied.
Data such as study design, study population and demographics,
and outcome measures were extracted. The primary outcome mea-
sures of interest were treatment response and safety/incidence of
adverse effects. Treatment response was quantified using standard-
ized mean difference (SMD) for mean reduction in Hamilton Rating
Scale for Depression (HAM-D) score from baseline with treatment.
Estimates were pooled and where appropriate, 95% confidence in-
tervals (CIs) and P values were calculated.
Heterogeneity among the different studies pooled was examined Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
using the I2 statistic and Cochran Q test. If heterogeneity was small flowchart showing the studies identified during the literature search and abstraction
(I2 50%), a fixed effects model was applied for the meta-analysis. process.
 Q.X. Ng et al. / JAMDA xxx (2017) 1e6
Fig. 2. Forest plot showing overall SMD for change from baseline HAM-D score, comparing curcumin with placebo/control.
to
0.129; P ¼ .002) indicate the significant clinical efficacy of cur-
cumin in ameliorating depressive symptoms when compared with
placebo/control. It is also noteworthy that curcumin demonstrated
significant anti-anxiety effects in 3 of the trials conducted.18,23,24
However, as curcumin was compared with placebo/control, it is un-
clear how curcumin may perform when compared with standard
SSRIs.
Various mechanisms of action for curcumin’s antidepressant ac-
tivity have been proposed, namely, the inhibition of monoamine ox-
idase A and B enzymes,27 modulation of neurotransmitter levels in the
brain,27,28 increasing brain-derived neurotrophic factor levels29 and
anti-inflammatory effects.30,31 The monoamine hypothesis32 and the
cytokine hypothesis33 of depression may help to explain curcumin’s
antidepressant effects. Based on the monoamine hypothesis, low
levels of monoamine neurotransmitters in the brain were responsible
for depression.34 Curcumin may increase the concentration of
monoamines available to interact with receptors, alleviating depres-
sion in the same way that tricyclic antidepressants do, as demon-
strated through in vitro and in vivo studies.19,27 The cytokine
hypothesis posits that raised inflammatory biomarkers called cyto-
kines often play a key role in the development of major depression.
Because studies show that curcumin strongly inhibits inflammatory
cytokines like nuclear factor-kappa B,35 NLRP3 inflammasome, and
interleukin-1B,36 this may help explain its antidepressant activity.37
Furthermore, laboratory studies with chronically stressed mice have
found that curcumin was able to reverse the effects of chronic stress on
behavior, the hypothalamic-pituitary-adrenal axis, and brain-derived
3
neurotrophic factor protein levels.38 Because depression is a risk fac-
tor for dementia,39 curcumin’s multifaceted neuroprotective effects
may further support its use for depressed patients. As first-line anti-
depressants such as SSRIs are lacking in their ability to effectively treat
cognitive symptoms,40 other drugs such as curcumin may be adminis-
tered alongside conventional therapy to enhance treatment outcomes.
This new approach to antidepressant medication was hailed by United
Kingdom researchers in the Psychiatric Research into Inflammation,
Immunity and Mood Effects consortium, who found that administering
anti-inflammatory drugs in combination with antidepressants could
significantly improve symptoms in patients with major depression.41
The large-scale Sequenced Treatment Alternatives to Relieve Depres-
sion trial also showed a strong need for sequential augmentation in the
treatment of major depression.42 In light of these findings, curcumin
could be used to augment or potentiate current antidepressant therapy
in the clinical setting, when first-line drugs fail.
Being a lipophilic substance, absorption of curcumin is better
with food,43 and curcumin is able to cross the blood-brain barrier
(and bind amyloid plaques44) and appears to be primarily concen-
trated in the hippocampus.45 However, a key limitation of curcumin
is its poor oral bioavailability and short retention time in the body
because of rapid breakdown in the liver and gut.43 To overcome this
problem, curcumin is often combined with piperine, a known in-
hibitor of hepatic and intestinal glucuronidation, or formulated as a
propriety highly bioavailable product such as BCM-95 (a patented
combination of curcuminoids and turmeric essential oils). A study,
which evaluated the bioavailability of curcumin and piperine co-
 4
Table 1
Characteristics of All Studies Included in this Meta-Analysis (Arranged Alphabetically by First Author’s Last Name)

Author, Year Study Design Study Sample Curcumin Dosage and Criteria for Diagnosis Outcome Measures Country of Origin Jadad Scale Conclusions
Duration

Bergman, 201322 Randomized, controlled, N ¼ 40 (17 males and 23 500 mg/d curcumin (with CGI-S 4 HAM-D17; CGI-S; MADRS; Israel 5 No significant difference
double-blind trial females), Mean age 50 mg of piperine) for HAM-D17 21 adverse events between curcumin and
65.8  10.7 (SD) 5 weeks MADRS 22 placebo. However, the
patients receiving
curcumin demonstrated a
trend to a more rapid
relief of depressive
symptoms than placebo.
No adverse effects
reported.
Esmaily, 201518 Randomized, double-blind, N ¼ 30 (6 males and 24 1 g/d curcumin (with 10 mg BDI BDI; BAI Iran 4 Nonsignificant effect on BDI
cross-over trial females), Mean age of piperine) for 4 weeks score, but significant anti-
38.8  11.1 (SD) anxiety effect.
Lopresti, 201423 Randomized, controlled, N ¼ 56 (16 males and 40 1 g/d curcumin (BCM-95Ò) DSM-IV IDS-SR30; STAI Australia 5 Curcumin was significantly
double-blind trial females), mean age for 8 weeks IDS-SR30 14 more effective than
44  12 (SD) placebo in improving

Q.X. Ng et al. / JAMDA xxx (2017) 1e6

Panahi, 201524 Randomized, open-label
trial
Sanmukhani, 201425 Randomized, controlled,
single-blind trial
Yu, 201526 Randomized, controlled,
double-blind trial
several mood-related
symptoms.
N ¼ 111 (51 males and 60 1 g/d curcumin (with 10 mg DSM-IV HAM-D; HADS; BDI; Iran 3 Significantly greater
females), mean age of piperine) for 6 weeks adverse events reductions in anxiety and
40.7  10 (SD) depression scores in the
curcumin vs control
group.
N ¼ 40 (16 males and 24 1 g/d curcumin (BCM-95) HAM-D17 7 HAM-D17; CGI-S; adverse India 3 The proportion of
females), mean age 40.4 for 6 weeks events responders was higher in
(range 34.1e46.7) the combination group
(77.8%) than in the
fluoxetine (64.7%) and the
curcumin (62.5%) groups;
but the difference was not
statistically significant
(P ¼ .58).
N ¼ 100 (100 males and 1 g/d curcumin for 6 weeks HAM-D17 10 HAM-D17; MADRS China 5 Significant reduction of
0 female), mean age MADRS14 depressive symptoms,
44.1  8 (SD) decreased inflammatory
cytokines interleukin 1b
and tumor necrosis factor
a level, increased plasma
brain-derived
neurotrophic factor
levels, and decreased
salivary cortisol
concentrations in
curcumin group
compared with placebo.

BAI, Beck Anxiety Inventory; BDI-II, Beck Depression Inventory II; CGI-S, Clinical Global Impression Severity Scale; DSM, Diagnostic and Statistical Manual of Mental Disorders; HAM-D17, Hamilton Depression Rating Scale 17-
item version; ICD, International Classification of Diseases; IDS-SR30, Inventory of Depressive Symptomatology e Self-rated; MADRS, MontgomeryeÅsberg Depression Rating Scale; STAI, State-Trait Anxiety Inventory; SD,
standard deviation.
 Q.X. Ng et al. / JAMDA xxx (2017) 1e6
Table 2
Results of Cochrane Collaboration’s Tool for Assessing Risk of Bias
Study (Author, Year) Sequence Generation Allocation Concealment
Bergman, 201322 þ þ
Esmaily, 201518 þ ?
Lopresti, 201423 þ þ
Panahi, 201524 þ e
Sanmukhani, 201425 þ e
Yu, 201526 þ þ
þ, low risk of bias; e, high risk of bias; ?, unclear risk of bias.
administered in rats and healthy human volunteers, found that
piperine enhances the serum concentration, extent of absorption,
and bioavailability of curcumin in both rats and humans with no
adverse effects.46 Laboratory studies have also demonstrated that a
curcumin-phospholipid combination can prolong the systemic
retention time of curcumin in rat serum,47 and curcumin-
encapsulated poly(lactic-co-glycolic acid) nanoparticles did not
offer significantly better blood-brain barrier penetration in rat
models but were retained almost twice as long in the cerebral
cortex and hippocampus.45
However, as there were only 6 clinical trials available, it is hard to
comment on any meaningful differences in results (and efficacy) in
humans according to the curcumin formulation.
With regard to the possible adverse side effects of curcumin,
though turmeric extracts have been found to be hepatotoxic in some
animals, human trials assessing the safety and toxicity of curcumin
demonstrated it to be safe, only occasionally resulting in slight
giddiness, nausea, and diarrhea.48 No adverse events were also re-
ported in any of the trials included in this meta-analysis. This means
that curcumin could be safe for use in elderly patients, even those
receiving multiple medications (polypharmacy). Nonetheless, quality
longitudinal studies are necessary to confirm the safety of curcumin
use. As with all natural plant products, issues that could arise from the
use of curcumin include potential drug interactions as well as the
variation in the formulation (and the general lack of regulation sur-
rounding curcumin use).
The limitations of this meta-analysis should be discussed. Because
of the small number of studies available, a funnel plot or sensitivity
analysis was not feasible. Future meta-analysis should include non-
English studies as some trials may have been missed in the search
process because of the language restriction. As the duration of all
available studies ranged from 4 to 8 weeks, it is also unclear if the
clinical improvement with curcumin use would be stable in the long
term. This is important as long-term treatment is often required in
the management of depression,49 hence, follow-up studies over a
longer duration should be planned. The generalizability of the find-
ings of this meta-analysis is also limited by the fact that the patients
in the trials reviewed had unipolar depression; it is, thus. unclear if
curcumin would have the same therapeutic effect for patients with
bipolar depression, or those with severe depression and high suici-
dality and suicide risk. Future research should address these ques-
tions and deficits.
Conclusions
Curcumin is a natural plant product with demonstrated antide-
pressant effects. Based on available clinical trials, the pooled SMD from
baseline HAM-D scores (pooled SMD
0.344, 95% CI
0.558 to
0.129;
P ¼ .002) supports the significant clinical efficacy of curcumin in
ameliorating depressive symptoms when compared with placebo/
control. Curcumin also appears to be safe and well-tolerated, with no
adverse events reported in any of the trials. For future studies, robust
randomized controlled trials with larger sample sizes and longer term
5
Blinding Incomplete Outcome Data Selective Outcome Reporting Other Bias
þ ? ? ?
þ ? ? ?
þ þ þ þ
e ? ? ?
e ? þ ?
þ þ ? e
or follow-up studies should be done to confirm that the clinical
improvement observed is stable in the long term.
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