Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-blind randomized controlled trial


Ashkan Heshmatzade Behzadi, No. 5/2, Amir Hamzeh Alamdari St, Bahar Shomali Ave, 7th Tir Sq, Tehran 15647-67411, Iran.


Objective:  The purpose of this study was to evaluate the efficacy of adding folic acid to sodium valproate in the acute phase of mania.

Method:  Following a double-blind randomized controlled trial, 88 clinically manic patients with diagnosis of type I bipolar disorder (BID) were divided randomly into two groups (case and control). The case group was treated with folic acid and sodium valproate and the control group with sodium valproate and placebo. The severity of mania was assessed using the Young Mania Rating Scale (YMRS) at the beginning and end of the first, second and third weeks of the study.

Results:  The case group’s mean manic YMRS measurements (SD) before the initiation of therapy and in the first, second and third weeks of treatment were 34.0 ± 7.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 respectively. The control group’s measurements were 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.5 and 10.1 ± 1.1. There was a statistically significant difference in YMRS scaling results between the case and control groups after 3 weeks of treatment (7.1 ± 0.9 vs. 10.1 ± 1.1, P = 0.005).

Conclusion:  Based on our findings, folic acid seems to be an effective adjuvant to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.

Significant outcome

  • • Better response to the treatment in patients with bipolar disorder using folic acid as adjuvant to sodium valproate in the acute phase of mania.


  • • Patients were followed up for 3 weeks and we suggest further studies with longer follow-up for evaluating the effect of folic acid on long-term treatment and the recurrence of bipolar disorder.


Lifetime prevalence of bipolar disorders ranges from 2.6% to 7.8% (1, 2). The association between nutrition, cognitive function and mood is a topic of public and psychiatric interest (3, 4).

It has been recently shown that cognition is impaired in many patients with bipolar disorder and recurrent unipolar depression during euthymic periods (5). Adequate levels of folate are crucial for proper brain and body functioning (6). Recent research has focused on the effects of the B vitamins and folate on cognitive disorders (4, 7, 8). These vitamins are of particular interest because of the high prevalence of mild to moderate subclinical deficiencies (9, 10). Research to date indicates some interlinked neurochemical mechanisms by which folate, with vitamins B12 and B6 as catalyzing co-factors, influences cognitive performance and mood (7, 11–14).

Studies have reported that patients with mood disorder such as major depression and both phases of bipolar disorder have low plasma, serum or red blood cell folate concentrations (15) and a recent trial on mood disorders showed beneficial results from supplementing antidepressant medication with folic acid (6). To date there has been no study to determine the effect of folic acid in the mania phase of bipolar disorder. This study is based on the assumption that there is a high prevalence of folic acid deficiency among patients suffering from mood disorders such as depression, mania and cognitive dysfunction disorders (11, 16–18).

Aims of the study

To evaluate the efficacy of using folic acid as an adjuvant therapy with sodium valproate in the manic phase of patients with bipolar disorder, in comparison with a control group treated with sodium valproate and a placebo.

Material and methods

The study was carried out in a double-blind randomized controlled clinical design. Eighty-eight patients were included in the study based on our inclusion and exclusion criteria (effect size: 0.3, power: 80%). Patients who were admitted to Iran Psychiatry Hospital, Iran University of Medical Science, with the primary diagnosis of manic disorder underwent a semi-structured interview on the basis of DSM-IV criteria, and after a definitive diagnosis of mania were included in the study. Side-effect onset of sodium valproate was an exclusion criterion. Other exclusion criteria were schizo-affective disorders, substance abuse and somatoform disorders. We also did not include patients with a history of using other mood-stabilizer drugs and we do not have any indication for changing these drugs to valproate. Patients with schizophrenia and organic mental disorders were excluded too. Antipsychotic treatment was not administered.

Patients were randomly divided into two groups (case and control). The case group was treated with sodium valproate and folic acid and the control group received sodium valproate with a placebo. The Young Mania Rating Scaling (YMRS) was designed for determining the severity of mania syndrome (19) with grading from 0 to 4. Severity of mania on the basis of the new version of Young Mania Rating Scaling (20) in each group was determined at the beginning of the study and after the first, second and third weeks of therapy. In most studies, the dosage range of folic acid in mood disorders is 2–15 mg (21–29). We gave 3 mg of folic acid to each manic patient in the case group. As the study design was double blind, physicians who prescribed the drug and nurses who administered it did not know the content of the administered medications (sodium valproate–placebo vs. sodium valproate–folic acid).

Data were collected using checklists for each group and were analyzed using the spss program (version 13; SPSS, Chicago, IL, USA). Tests used in the analysis included t-tests, anova, logistic regression, correlation and chi-squared tests. The study was approved by the Ethics Committee of Iran University of Medical Sciences.


Eighty-eight patients with BID (mean age 35.0 ± 8.4 years, M/F 1.4) were randomly divided into two groups. The two groups were similar regarding their age (P = 0.31), gender (P = 0.45), mean dosage of sodium valproate (1180 ± 240 mg vs. 1300 ± 300 mg, P = 0.68) and the initial YMRS scores (P = 0.74). From 44 patients in each group, 41 (93.2%) patients in the case group and 43 (97.7%) patients in the control group finished the protocol successfully. Two cases had liver enzyme rising, one patient had severe rashes and another patient had agranolucytosis. These were excluded from the study.

The mean YMRS ratings of manic patients, before the initiation of the trial and at the end of the first, second and third weeks of treatment in the case group were 34.0 ± 3.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 and in the control group 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.9 and 10.1 ± 1.1 respectively (Table 1).

Table 1.   Subscale values (Young Scale) in different trial steps for both case and control groups
SubscaleBaseline valueFirst weekSecond weekThird week
  1. *P < 0.001; **P = 0.003; ***P = 0.005.

1. Elevated mood (0–4)2.8 ± 1.43.1 ± 1.22.4 ± 0.92.3 ± 0.781.5 ± 0.71.8 ± 0.60.4 ± 0.40.6 ± 0.34
2. Increased motor activity and energy (0–4)3.8 ± 1.93.7 ± 2.12.7 ± 1.13.3 ± 1.72.2 ± 0.92.4 ± 1.20.9 ± 0.31.2 ± 0.5
3. Sexual interest (0–4)3.6 ± 1.73.9 ± 1.93.2 ± 1.73.4 ± 1.52.1 ± 1.12.4 ± 0.91.1 ± 0.71 ± 0.6
4. Sleep (0–4)2.7 ± 1.03.1 ± 1.32.3 ± 0.82.5 ± 0.81.4 ± 0.92.1 ± 1.10.5 ± 0.30.9 ± 0.4
5. Irritability (0–4)2.6 ± 0.82.8 ± 1.41.6 ± 0.51.5 ± 0.71.1 ± 0.51.4 ± 0.40.2 ± 0.1*0.5 ± 0.1
6. Speech (0–4)2.7 ± 1.42.4 ± 1.21.6 ± 0.71.8 ± 0.61 ± 0.51.2 ± 0.50.3 ± 0.40.6 ± 0.3
7. Language and thought disorder (0–4)3.4 ± 1.23.0 ± 1.13.0 ± 0.62.9 ± 0.41.7 ± 0.42.1 ± 0.60.6 ± 0.2**1.1 ± 0.2
8. Thought content (0–4)3.1 ± 0.93.5 ± 1.31.9 ± 0.42.1 ± 0.51.2 ± 0.41.5 ± 0.40.4 ± 0.31 ± 0.20
9. Disruptive–aggressive behavior (0–4)2.9 ± 0.93.1 ± 1.11.8 ± 0.62.2 ± 0.81.1 ± 0.51.6 ± 0.60.6 ± 0.21.1 ± 0.2
10. Appearance (0–4)3.2 ± 1.83 ± 1.63 ± 1.82.3 ± 1.42.1 ± 0.92 ± 0.71.2 ± 0.51 ± 0.3
11. Insight (0–4)3.2 ± 1.93.1 ± 1.53.2 ± 1.73 ± 1.32.7 ± 0.82.2 ± 0.70.9 ± 0.41.1 ± 0.4
Total scale (0–44)34 ± 3.734.7 ± 3.826.7 ± 2.127.3 ± 2.318.1 ± 2.120.7 ± 2.57.1 ± 0.9***10.1 ± 1.0

In the control group, the difference in mania score before and after treatment was significant (34.7 vs. 10.1, P < 0.001). Patients in the case group also had a statistically significant difference in the severity of the disorder before and after treatment (34.0 vs. 7.1, P < 0.001).

The severity of mania (on the basis of YMRS scaling) after 3 weeks of therapy with sodium valproate and a placebo in the control group was 10.1 ± 1.1 and in the case group was 7.1 ± 0.9 (P = 0.005, Table 1).

Subscale analysis revealed that language and thought disorder (P = 0.003), irritability (P = 0.001), thought content (P = 0.001) and disruptive–aggressive behavior (P = 0.001) were the only subscales which were significantly different after 3 weeks of treatment (Table 1).


This study showed a statistically significant difference between the case and control groups in response to the treatment. Patients experienced greater improvement with the adjunction of folic acid to sodium valproate in the treatment of the mania phase of bipolar disorder. This difference was significant only after 3 weeks of therapy in some subscales including language and thought disorder, irritability, thought content and disruptive–aggressive behavior.

Most of previous studies about the effect of folic acid on mood disorder focused on depressed patients. These studies reported that depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency (2, 6, 15, 16, 30). Regarding these findings, researchers concluded that folate may have a potential role as a supplement to other treatments for depression, but it was currently unclear if this is the case for both people with normal folate levels and with folate deficiency (15, 31). A recent study in this matter showed that treatment with folic acid improves response to antidepressants (32).

Poor health behaviors such as poor nutrition are prevalent among patients with bipolar disorder (33–35). Elevated homocysteine levels may also be due to poor self-care and/or dietary habits, which may in turn influence the severity of illness (35). Methylene tetrahydrofolate reductase (MTHFR) activity is related to high homocysteine levels, associated with bipolar disorder (36, 37). A more recent study confirms that, in patients with bipolar disorder, higher homocysteine levels are associated with poorer performance in some neuropsychological tests (38).

Regarding these basic findings it has been suggested that the best way forward may be to undertake large-scale community-based studies of folate supplementation or food fortification to explore the preventive potential of vitamins for mood and cognitive disorders (16). Among both depressed and patients with schizophrenia, folic acid significantly improved clinical and social recovery. This indicates the probable beneficial effect of administration of folic acid for major depression and also bipolar disorders (39).

Stern et al. (40), McKeon et al. (12) and Coppen and Bolander-Gouaille (38) reported more folate deficiency in unipolar depressive patients compared with that in patients with bipolar disorder. In contrast to all previous studies, the current study is the first trial showing a significant effect of folic acid in the improvement of manic patients treated with sodium valproate.

In this study, we used the new version of the Young Scale for evaluating of our patients (all of 11 items have the same scale, 0–4). This is different from previous studies that used the previous version of the Young Mania Rating Scale. Originally, this scoring system was recommended to compensate for the poor cooperation seen in severely ill patients (19). However, the most recent publication by Young et al. regarding their scale (20) states that the inclusion of four items with scores ranging from 0 to 8 rather than 0 to 4 leads to some confusion.

We need further studies to get more information about the effect of folic acid in the treatment of other mood and cognitive diseases. We also suggest further studies to evaluate long-term effects of folic acid in the treatment of bipolar disorders. It is currently still unclear whether the result in this matter is applicable both to people with normal folate levels and to those with folate deficiency. The circumstances under which folate and its derivatives may have a role in mood stabilizer pharmacotherapy must be further clarified. In conclusion, based on our findings, folic acid seems to be an effective adjuvant supplement to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.


The authors are grateful to Mr Dennis Wilson for his assistance in process of this study.