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The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A randomized controlled study

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Letter to the Editor
The effects of curcumin on brain-derived
neurotrophic factor and cognition in
schizophrenia: A randomized
controlled study
Keywords:
Curcumin
Schizophrenia
BDNF
Cognition
Curcumin is a polyphenolic compound derived from the spice tur-
meric (Curcuma longa) with potential as a complementary treatment
for people with schizophrenia. In preclinical studies, curcumin has
been reported to have anti-oxidant, anti-inammatory, neuroprotec-
tive, and pro-cognitive properties, as well as increased levels of brain-
derived neurotrophic factor (BDNF) (Dong et al., 2012; Fanaei et al.,
2016; Motaghinejad et al., 2017). The effects of curcumin on BDNF
and neurocognition are particularly relevant for schizophrenia as well-
documented lower levels of BDNF and neurocognitive decits have
been reported (Green et al., 2011).
We examined the effects of curcumin in patients with schizophrenia
in an 8-week randomized, double-blind, placebo-controlled study,
assessing BDNF levels, clinical symptoms, and measures of social and
non-social cognition. We hypothesized that curcumin would increase
BDNF levels and improve cognitive performance.
Forty-ve stable, medicated outpatients meeting DSM-5 criteria for
schizophrenia were recruited from the VA Greater Los Angeles
Healthcare System (VAGLAHS) and outpatientclinics in the Los Angeles
area. All participants had the capacity to give and provided written in-
formed consent in accordance with procedures approved by the Institu-
tional Review Board at VAGLAHS. This study was registered with
ClinicalTrials.gov (identier: NCT02104752).
Curcumin capsules and matched placebo were provided by
Theravalues Corporation (Tokyo, Japan). Subjects randomized to
curcumin received 360 mg/day (divided into twice daily oral doses);
those randomized to placebo receivedan equal number of capsules. Par-
ticipants received clinical and cognitive assessments as well as blood
draws at baseline (prior to study treatment), and at 4- and 8-weeks
post baseline.
Serum BDNF levels were analyzed by the UCLA Immunogenetics
Center/UCLA Immune Assessment Core. Analysis was performed on
human serum samples with the Human BDNF Quantikine ELISA (R&D
Systems, Minneapolis, MN). Results are reported in pg/mL.
The MATRICS Consensus Cognitive Battery (MCCB) was used to as-
sess non-social cognition. Age and gender-corrected normed T-scores
for the global composite were analyzed. The Empathic Accuracy task
(Kern et al., 2013) was used to assess social cognition. For symptom as-
sessments, we used the Brief Psychiatric Rating Scale and the Clinical
Assessment Interview for Negative Symptoms.
For analyses, we used a generalized linear mixed model, which in-
cluded xed effects for time, treatment and treatment-by-time interac-
tions, and a random intercept term for each participant. The primary
effect of interest was the treatment-by-time interaction as it models dif-
ferences in change over time that can be attributed to treatment.
Thirty-six patients (curcumin n = 17, placebo n = 19) had useable
data. For BDNF, there were no signicant main effects of treatment
or time. However, the treatment × time interaction was signicant,
F
1,69
= 4.23, p = 0.043. Patients receiving curcumin showed increased
levels of BDNF relative to baseline, whereas patients receiving placebo
showed declines relative to baseline (Fig. 1). There were no signicant
differences in BDNF levels between the curcumin and placebo groups
at baseline. The treatment × time interactions for symptoms and cogni-
tion were not signicant.
This is the rst study evaluating the effects of curcumin on BDNF, and
clinical and cognitive measures in patients with schizophrenia. In this
study, curcumin increased BDNF levels over the treatment period, com-
pared to placebo. These results demonstrate that curcumin may have a re-
liable biomarker in its effects on BDNF, but did not show more distal
effects on cognition or clinical symptoms for patients with schizophrenia.
While the exact mechanism through which curcumin can increase BDNF
levels is unknown, it may work through enhanced expression of the BDNF
gene via phosphorylated cAMP response element-binding protein (CREB)
(Xu et al., 2006). As alterations in CREB have been noted in people with
schizophrenia (Ren et al., 2014), curcumin could potentially reverse
these decits, thereby leading to increased expression of BDNF.
A major limitation in clinical trials of curcumin has been poor ab-
sorption and bioavailability of earlier preparations of curcumin (Gupta
et al., 2013), as well as rapid metabolism by the liver and intestine.
We used a formulation of curcumin nanoparticles (Theracurmin)
which is highly bioavailable and well-tolerated in humans (Sasaki et
al., 2011). As this was a preliminary study with a modest sample size,
we did not have sufcient power to detect small differences in cognition
and symptoms. The results of the current study should be interpreted
with caution until replication with larger sample sizes.
These results are promising regarding a proximal biomarker, BDNF,
and may have long-term benets for cognition and symptoms that
would not be observable in an 8-week trial. Because the development of
schizophrenia has been linked to increased inammatory response, oxi-
dative stress, and abnormal neural pruning (Barron et al., 2017), a thera-
peutic agent that alleviates one or more of these by increasing BDNF could
protect processes (e.g., poor learning, memory, neuroplasticity) impacted
by the disease.
Conict of interest
In the past3 years, MFG has received researchsupport from Forum, has been a consul-
tant for AbbVie, ACADIA, DSP, and Takeda; and is on the scientic board of Luc. SRM has
received research support from Neurocrine and Fo rum and has been a consultant for
Allergan, Teva, Takeda, Roche, Lundbeck, Jazz, and Forum. The remaining authors report
no conict of interest.
Schizophrenia Research xxx (2017) xxxxxx
SCHRES-07560; No of Pages 2
Clinical trial registration: Curcumin as a Novel Treatment to Improve Cognitive
Dysfunction in Schizophrenia, http://clinicaltrials.gov/,ClinicalTrials.gov identier:
NCT02104752.
https://doi.org/10.1016/j.schres.2017.09.046
0920-9964/Published by Elsevier B.V.
Contents lists available at ScienceDirect
Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres
Please cite this article as: Wynn, J.K., et al., The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A ran-
domized controlled study, Schizophr. Res. (2017), https://doi.org/10.1016/j.schres.2017.09.046
Contributors
Drs. Wynn, Davis, and Marder designed the study. Drs. Wynn and Hellemann con-
ducted the data analyses. Miss Karunaratne collected blood samples and assisted with
BDNF and other statistical analyses. Dr. Wynn wrote the rst draft of the manuscript.
Drs. Wynn,Davis, Green, andMarder edited themanuscript and helped with the interpre-
tation of the ndings. All authors contributed to and have approved the nal manuscript.
Funding and disclosures
This work was supported by grant 13T-003 from the Stanley Medical Research Institute
(JKW and SRM, co-PIs), NIMH Grant R01 MH095878 (MFG, PI), and by a Department of Vet-
erans Affairs Research Enhancement Program (MFG, PI). Theravalues Corporation (Tokyo,
Japan) generously donated drug and matched placebo capsules. The funding agencies and
Theravalues Corporation had no further role in the design, analysis, interpretation, or deci-
sion in publication of this study. For Michael C. D avis, participation occurred prior to his cur-
rent position. The contents herein do not represent the views of the U.S. Department of
Veterans Affairs, the U.S. Food and Drug Administration, or the United States Government.
Acknowledgements
The authorswould like to thank Theravalues Corporation (Tokyo,Japan) for their gen-
erous donation of drug and matched placebo pills. The authors would also like to thank
Aaron McNair and Gabrielle Pascual for assistance with data collection and entry.
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Jonathan K. Wynn*
Michael F. Green
Mental Illness Research, Education and Clinical Center, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
Corresponding author at: VA Greater Los Angeles Healthcare System/
UCLA, MIRECC, Bldg. 210, Rm. 115, 11301 Wilshire Blvd., Los Angeles, CA
90073, USA.
E-mail address: jkwynn@ucla.edu (J. K. Wynn).
Gerhard Hellemann
Kumari Karunaratne
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
Michael C. Davis
United States Food and Drug Administration, Silver Spring, MD, USA
Stephen R. Marder
Mental Illness Research, Education and Clinical Center, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
14 June 2017
Available online xxxx
Fig. 1. Mean blood serum levels(pg/mL) at baseline(time 0) and at 4- and 8-weeks of treatmentfor schizophreniapatients on curcumin(solid line) or placebo (dashed line). There wasa
signicant interaction (p = 0.043) such that curcumin resulted in increased BDNF at 4- and 8-weeks of treatment whereas there the placebo group showed decreased BDNF over time.
2Letter to the Editor
Please cite this article as: Wynn, J.K., et al., The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A ran-
domized controlled study, Schizophr. Res. (2017), https://doi.org/10.1016/j.schres.2017.09.046
... Zhu et al. published a meta-analysis investigating the effect of curcumin on cognition in 2019 [12], summarizing the RCTs available between 2008 and 2018 [10,11,[13][14][15][16]. They also performed a subgroup analysis according to participants based on the presence of older age, Alzheimer's disease, and schizophrenia. ...
... One article was excluded because it was a review of an already-included RCT [25] (Table S3). Finally, eight articles were included [10,11,13,15,16,[26][27][28]. The clinical trial registry data of these eight articles were also checked and analyzed for qualitative and quantitative analyses [29][30][31][32][33][34][35]. ...
... The study duration ranged from 8 to 18 months. The enrolled subjects included older adults in four studies [11,15,27,28], patients with Alzheimer's disease in two studies [10,13], and patients with schizophrenia in two studies [16,26]. The curcumin formulations were Theracumin ® in three studies [15,16,26], Brain Active ® in one study [28], Longvida ® in one study [27], Biocurcumax ® in one study [11], Curcumin C3 Complex ® in one study [10], and powders of Kancor flavors or capsules of Arjuna Natural Extracts in one study [13]. ...
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