The effect of adding curcumin to sodium valproate in treatment of patients with bipolar disorder in the acute phase of mania: a clinical trial.

Background: Inflammatory processes in the brain play an important role in etiopathogenesis of many psychiatric disorders including, bipolar mood disorder (BMD) as a life-long episodic disease. An inefficient therapeutic intervention especially for resistant cases makes the necessity of doing more precise investigation to find out new therapeutic approaches apparent. This double-blind study aims to investigate the effect of Crucumin as anti-inflammatory herbal based drug in the treatment of BMD. Results: 78 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for BMD screening to participate in the trial. The participants included 32 patients in the placebo group receiving sodium valproate and crucumin and 38 patients in the control group receiving placebo and sodium valproate. At the beginning of the study and weeks 1, 2, 4 the patients were assessed by a psychiatrist using Young mania score (YMRS). Fifty four patients completed the trial. Mean age in patients group was 36.28±10.73 and in control group was 32.42 ±9.60.Clinical characteristics of the patients, such as age, did not differ between groups P value ≥0.05. Results showed the process of changes were significant different in both group. The results showed that the changes in the resultss of YMRS, MMSE and CGI scores were significant in each group (P value≤0.001), but no significant difference has been detected between the two groups (p≥0.05). Conclusions: this study suggested that crucumin cannot be an effective adjuvant agent in management of patients with BMD under treatment with sodium valproate.

concerning the bipolar disorder's prevalence (1.5%), disorder's suicidal rate (10-20% ), high recurrence of this disorder ,half effectiveness of single-drug therapy, as well as considering inefficient therapeutic interventions such as drug augmentation for managing resistant to response cases ; The necessity of doing more precise investigation to find out new therapeutic approaches is apparent .1 Various studies have found that serum BDNF levels decreased in bipolar disorder (2). Curcumin like the well-known treatments of this disorder (lithium, etc and atypical antipsychotics) can increase BDNF levels. (3)(4)(5) There is much evidence that oxidative stress mechanisms have been involved in bipolar disorder (6,7). In this way, increasing ROS production lead to the lack of antioxidant mechanisms resulting in apoptosis, necrosis and brain damage (6)(7)(8)(9).
Studies have shown that curcumin has antioxidant function which can reduce ROS (10,11) Inflammatory processes affect neurotransmitter function and neuronal plasticity (12,13) which play a noteworthy role in the pathophysiology of neurodegenerative diseases (14). Increasing of CRP, inflammatory cytokines and TNF alpha occur in bipolar disorder can be reduced by curcumin (15,16). There is also evidence about impairment of apoptosis in psychiatric diseases, which leads to an increase in cell death (17,18). Curcumin can regulate these mechanisms (19).
Since the ancient Persian medical texts have highlighted the anti-inflammatory effects of turmeric, many studies have been carried out on this subject. However, limited studies have been performed to evaluate its effects on dipolar disorder. The purpose of this study was to determine the effect of adding curcumin to sodium valproate in the treatment of patients with bipolar disorder in the acute phase of mania.

Material and Method:
This study is a double-blind clinical trial performed during 1396 − 1395. Initially, 78 patients aged 18 to 50 years old diagnosed with bipolar mood disorder, based on DSM 5 criteria, And according to the inclusion criteria of current study, were participated in this study.

Inclusion criteria:
The age of the subjects was 18 to 59 years old Diagnosis of bipolar-1 disorder with recent episode mania based on DSM-5 diagnostic criteria by Semi-structured interview done by a psychiatrist and diagnostic confirmation with a score of at least 20 of Young mania score (YMRS) (20) The absence of the diagnosis of schizophrenia, delirium, bulimia nervosa, anorexia nervosa, mental retardation, autism, substance abuse (at least 3 months ago), ADHD.
No history of admission to the psychiatric ward during the past three months No history of seizure or epilepsy the absence of suicidal or homicidal risk during the psychiatric interview Women suspected to be pregnant will undergo a pregnancy test and, if positive, be excluded from the study.
Lack of a history of susceptibility to sodium valproate or any herbal medicines.
Patients who have received other medications during the last two weeks prior to study or during the study, including mood stabilizer treatments that cannot stop them. The washout period will be considered based on the medication's half-life for patients receiving drugs with a long halflife.
A full interview was conducted for each patient by a psychiatric resident (based on inclusion and exclusion criteria) and diagnostic suspicion cases were excluded from the study. The informed consent was obtained from eligible patients. (Or their legal guardians) Patients who agreed to participate in our trial were randomly assigned into two groups using randomized number table. Patients in the intervention group besides receiving sodium valproate (starting at a dose of 600 mg / day and administrate up to 20 mg / kg / day or the highest dosage of the patient's tolerance), received curcumin drug while control group received placebo in addition to sodium valproate . Placebo soft gels were made by the same manufacturer of soft curcumin gels, having the same size, color and smell. Soft curcumin gel has 40 mg Nanomycesel, absorbed as equivalent to 500 mg curcumin tablets. For describing the data, descriptive statistics including frequency tables, diagrams, and statistical indicators were used, and data analysis was done using SPSS software version 11.5.
To analyze the data, Kolmogorov-Smirnov test, Mann Whitney test, independent Ttest, Fisher's exact test and chi-square were applied. A p-value less than 0.05 were taken as mean statistical significance. To control and determine the effect of confounding variables in case of heterogeneity between two groups, appropriate statistical tests such as covariance or logistic regression were used.
Since this research was conducted for the first time and no similar research to ours has been done yet, with regard to the goals mentioned so far, sample size calculations cannot be used by statistical formulas. Therefore, this study was done as a preliminary study with a sample size of 20 people in each group, that is, a total of 40 cases.
Results: 78 cases were screened for participating in this study among those 8 cases who were reluctant to participate in the study, 8 cases for discontinuing sodium valproate, 2 patients due to change of the diagnosis or therapeutic regime and 4 cases due to lack of cooperation has been excluded from the study, while 54 cases continued The study till the end. (Fig. 1 includes the consort flow diagram of the trial).As you can see Table 1 includes Patient's demographic data comparison between two groups.   Although the descending Progression of young scores in each group was significant (p-value: 0.00), No significant difference between the two groups was considered after 4 weeks. (P value: 0.64)( Table 3) Table 4 Average CGI scores in both intervention and control groups.  While the percentage of response to treatment in the intervention group was higher than control group, Fisher's exact test didn't confirm any significant difference between two groups. (P-value: 0.49)( Table 5) Table 6 Evaluating the Subsidence of symptoms in both intervention and control groups. In both groups, more than half of the patients have reported the subsidence of symptoms which was higher in the intervention group comparing to the other one, But as well as response to treatment results, the Fisher's exact test was not meaningful between two groups.( P value: 0.75) ( Table 6)   Table 7 The frequency of the severity of disease and MMSE score in both intervention and control groups at the beginning of the study.  As mentioned, doing researches to find out an effective medical treatment seems to be necessary while preserving various dimensions of personal and social life of patients from disorder's full influenced cost.

Subsidence of symptoms
Psychopharmacological treatments are the first line for treating this disorder. So far, mood stabilizers including carbamazepine, sodium valproate and some types of antipsychotics have been used to treat acute phase of mania.1 The lack of proper response to existing drugs among significant numbers of patients, makes inventing new medicines for treating these patients as well, a main concern for many scientist.
The results of laboratory researches demonstrated that the increased activity of the hypothalamus axis in mood disorders including bipolar disease leads to changes in the level of many inflammatory cytokines .23 Regarding the role of inflammation in the pathophysiology of the bipolar disease, several studies, indicated the efficacy of anti-inflammatory drugs in affected patients. Some studies show that curcumin inhibits the expression of COX2 and the production of cytokines such as interferon-gamma and interleukin-6 which results in inhibiting the inflammatory responses.
Part of the anti-inflammatory effects of turmeric may be due to the inhibitory effects of curcumin on the activity of the hyaluronidase enzyme.24 In a review study done by Brietzke and coleague in 2013, evaluated the curcumin's anti-inflammatory and anti-oxidant properties. Discussing its therapeutic prospective in Bipolar disorder they find out that this agent is notably affecting on depressive symptoms and cognitive impairment. Although they suggested further clinical trial to be done for supporting this issue, the demonstrated that many CAM (complementary and alternative medicines) turned out to be ineffective at best and damaging at worst in treating Bipolar disorder. 32 Now a day the issue of complementary usage of herbal and ancient medicine in modern practice has become the topic of the day, thus many researchers try to use ancient herbal medicine in new pharmacological forms in order to find out a relief pathway in treating disorders. The purpose of this study was to explore whether curcumin as widely-mentioned anti-inflammatory herbal based drug, has an effect on bipolar disorder treatment or not.
The results of our study showed significant reduction progress in young mania score after 4 weeks of receiving the curcumin versus placebo in each group. Although the intervention group shows a higher response to treatment and subsidence of symptoms, this difference was not statistically significant comparing to control group. Also, the results of patients' overall function and cognition (CGI and MMSE scores) after 4 weeks showed a significant improvement in each group, but this improvement was not statistically meaningful between the two groups.
Studies have claimed curcumin's anti-inflammatory effects in deactivating free radicals and its anticancer effects have been proven which are mainly due to its effect on intracellular enzymes & inhibition of signaling pathways at various levels.
These effects of curcumin are often dose and environmental-condition dependent.24-26 The curcumin therapeutic effects appear to be because of its neuroprotective and antioxidant effects which increase the level of neurotrophic factors. Given the low bioavailability of the drug, it seems necessary to increase the dose. Concerning other studies, a dose of 500 mg per day which was used in ours also seems to be a low dose of curcumin. 30 − 27 In the present study, the drug dosage was much lower than other studies which may also affect the patients' lack of response. In most studies, the recommendation is to start with a dose of 20 mg based on weight and increase to a dose of 80 mg per kg, which is about 1500 mg per day (31) Conclusion: The results of our study showed higher response to treatment, subsidence of symptoms and improving in patients' overall function and cognition after 4 weeks of receiving the Curcumin but this improvement was not statistically meaningful.
According to our study Curcumin add-on therapy doesn't seem effective in treating acute phase of mania in patients with bipolar disorder.

Limitations
The limited small sample size and the fixed dosage of the curcumin were our study's constraints. We suggested the use of higher doses of curcumin which is better to be administrated according to the curcumin serum level, in the future studies.

Declarations
Ethics approval and consent to participate: All participants voluntarily and consciously participated in our study. After obtaining the scientific approval by the psychiatric Department, the proposal of this thesis research was offered to the Ethics Committee of Mashhad University of Medical Sciences.
Indeed, the participants were completely informed about the aim and the method of our study, and an informed consents have been taken orally and written in patients' native language (Persian) prior to the study.All participants' were assured that their information was kept confidential and they were able to leave the study at any time.
Furthermore, patients who needed urgent intervention or suspected to intensifying symptoms by the treatment used in our research, were excluded from the study.

Consent for publication:
"Not applicable" Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests.

Funding
No funding was received. The consort flow diagram of the trial