A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes

A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes

Journal of Affective Disorders 150 (2013) 644–648 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.els...

500KB Sizes 12 Downloads 305 Views

Journal of Affective Disorders 150 (2013) 644–648

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Brief report

A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes Ramakrishnan Venkatasubramanian, Channaveerachari Naveen Kumar n, Ravi Shankar Pandey National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 October 2012 Received in revised form 19 February 2013 Accepted 20 February 2013 Available online 15 March 2013

Background: Though encouraging evidence exists for the use of folic acid as an augmenting agent to antidepressants, evidence regarding its optimal dosage is lacking. Methods: Forty-two female out-patients with moderate (with or without somatic syndrome) or severe depressive episodes (without psychotic symptoms) diagnosed as per ICD-10 criteria, were randomized in a double-blind fashion to receive either 20 mg fluoxetine and a relatively low dose folic acid (1.5 mg/ day; n ¼ 23; Group I) or 20 mg fluoxetine and high dose folic acid (5 mg/day; n ¼ 19; Group II). Primary outcome measures were weekly changes of scores on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) for 6 weeks. Results: Group II patients showed greater improvement in both HDRS [Mean (SD) baseline HDRS score ¼ 21 (2.3) for group I and 20.0 (1.4) for group-II; time X group interaction effect: p¼ 0.01] and BDI [Mean (SD) baseline BDI score ¼ 25.1 (5.2) for group-1 and 23.1 (2.7) for group-II; time X group interaction effect: p ¼ 0.01]. With regard to HDRS, 7 (36.8%) group II patients remitted compared to 2 (8.7%) group I patients (p¼0.03); 9 (47.4%) patients of group II responded when compared to 6 (26.1%) from group I (p ¼ 0.15). When BDI was considered, 5 (26.3%) group II patients remitted when compared to 2 (8.7%) from group I (p ¼0.13); 10 patients (52.6%) from group II responded when compared to 5 (21.7%) from group I (p¼ 0.04). No adverse effects were noted in either group. Limitations: Lack of a placebo arm and small sample size. Conclusion: Compared to folic acid 1.5 mg/day, augmentation with 5 mg/day may be more beneficial in female patients with depressive episodes taking fluoxetine 20 mg/day. & 2013 Elsevier B.V. All rights reserved.

Keywords: Depressive episodes Fluoxetine Augmentation Folic acid Folate

1. Introduction Encouraging evidence exists for the use of omega-3 fatty acids, S-Adenosyl methionine, folic acid and L-tryptophan adjuvant with antidepressants to enhance response and improve efficacy (Sarris et al., 2010). Folic acid in its various forms (folic acid, methylfolate and folinic acid) (Fava and Mischoulon, 2009) has been found useful as an augmenting agent to antidepressant medications. For example, Godfrey et al. (1990) randomized patients with DSM III diagnosis of major depression as well as schizophrenia to receive either methyl folate (n ¼22 inclusive of both patients in the active treatment arm) or placebo (n ¼19 in this placebo arm) in addition to the psychotropic that they were getting. The trial went on for 6 months. Among both depressed and schizophrenia patients, methyl folate significantly improved

n Correspondence to: Department of Psychiatry, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, India. Tel.: þ91 80 26995254; fax: þ91 80 26564830. E-mail addresses:[email protected], [email protected], [email protected] (C.N. Kumar).

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.02.029

clinical and social recovery. In addition, the differences in outcomes became greater with time. Coppen and Bailey (2000) randomized 127 patients with DSM III R major depression to receive either folic acid (500 mcg/day) or placebo in addition to fluoxetine 20 mg/day. Results showed that overall patients receiving folate showed a significant increase in plasma folate. Statistically significant magnitude of improvement was noted for the fluoxetine plus folic acid group only in women. This result held true among both responders as well as remitters. Passeri et al. (1993) in a randomized double-blind study involving patients with organic depression showed that folate improved the HDRS scores better than Trazadone. Another trial involving 27 depressed subjects found that 20 mg of fluoxetine combined with 10 mg of folic acid was more effective in reducing Hamilton Depression Rating Scale (HDRS) scores compared to augmentation with placebo (final HDRS scores 7.4371.65 vs. 11.43 71.31, respectively; p ¼0.04). A significant reduction of homocysteine was also observed in the folic acid group, compared to placebo (Resler et al., 2008). However, more information about its optimal dosage is required (Fava and Mischoulon, 2009). The dosage of folic acid or its equivalent has

R. Venkatasubramanian et al. / Journal of Affective Disorders 150 (2013) 644–648

Here, we would like to note that none of the patients had any neurological deficits. Moreover macrocytic anaemia was ruled out by estimating haemoglobin and mean corpuscular volume whose normalcy substantially excludes clinically significant vitamin B12 deficiency. In the latter case, addition of folic acid without vitamin B12 is not desirable as is well known. Diagnosis of depressive disorders was done by clinical interviewing. The 17 item version of the HDRS (Hamilton, 1960) and Beck Depression Inventory (BDI) (Beck et al., 1961) were used to assess change in depression scores over 6 weeks of treatment period. With regard to HDRS, response was defined as 50% reduction in HDRS scores from the baseline (Lam and Kennedy, 2004) and remission was defined as a score o8 (Kelsey, 2002). With regard to BDI, a score of less than nine from baseline was defined as remission (Keller, 2003) and 50% reduction of symptom score was considered as response (Vergouwen et al., 2007). These response and remission criteria were apriori decided. In this dose-response study, assessments were carried out at baseline and weekly intervals. These 42 patients were randomly assigned to one of the two treatment groups: low dose folic acid group (Group I; fluoxetine 20 mg/day þ1.5 mg folic acid/day) and high dose folic acid group (Group II; fluoxetine 20 mg/day þ5 mg folic acid/day). Folic acid or pteroylglutamic acid (PGA) was prepared as identical looking capsules in two dosage forms as 1.5 mg and 5 mg. British Pharmacopoeia preparation of folic acid was used for this study. Neither the rater (RV) nor the patients knew the group status. One of the authors (RSP) labelled the vials containing study medications using random numbers from a computer generated random number table and kept the key. The folic acid tablets were identical looking. The rater was not aware of the allocation sequence. After data collection was completed, this key was used to ascertain the group status of patients. In this way, allocation concealment was also ensured. Same rater evaluated the patients from beginning till the end.

widely ranged between 0.2 mg and 105 mg in various studies (Coppen and Bailey, 2000; Godfrey et al., 1990) if we consider that 1 mg of methyl-folate is equivalent to 7 mg of folic acid (Willems et al., 2004). In view of such wide range, it has been suggested without adequate experimental work that 2 mg of folic acid may be given for augmentation of antidepressant response (Abou-Saleh and Coppen, 2006). Since we could not come across any study which has compared the add-on effect of the relatively low (1.5 mg/day) versus high (5 mg/day) dose folic acid, we conducted this study with the aim of comparing the add-on effect of these two doses of folic acid in patients suffering from depressive episodes.

2. Methods This study comprised consecutive 42 female out-patients who consulted National Institute of Mental Health and Neurosciences, Bangalore, a state funded tertiary care neuropsychiatric centre between May 2006 and May 2007. The study was approved by the Institutional Ethics Committee. Patients currently satisfied ICD-10 (WHO, 1992) criteria for the diagnosis of: (a) moderate depressive episode with or without somatic symptoms or (b) severe depressive episode without psychotic symptoms. Patients with first episode of depression and also those with recurrent episodes were included. For inclusion in this study, the patient had to satisfy the following additional inclusion criteria. Bipolar depression was an exclusion criteria. 1. 2. 3. 4.

5. 6.


8. 9.


Aged between 16 and 45 years Provision of written informed consent Scores of at least 18 on Hamilton depression rating scale Absence of symptoms necessitating alternate treatment like suicidal ideation (score of at least three on item no 3 of HDRS), stupor Haemoglobin level of 410 g%, mean corpuscular volume not exceeding 100 fl, normal peripheral smear Drug free state for 8 weeks. For the purpose of this study, a patient who had received antidepressants, benzodiazepines or neuroleptics (non-depot) for four days or more during the past 8 weeks was considered as drug free No contraindication to fluoxetine therapy: e.g., history of acute gastritis, duodenal ulcer, severe reflux oesophagitis or intolerance/ allergy to fluoxetine in previous episodes of depression or history of non-response to fluoxetine in previous depressive episodes Absence of any psychiatric comorbidity as assessed by detailed clinical interview Absence of any physical comorbidity as assessed by history/ physical examination

3. Statistical analysis Continuous variables were analysed using the independent sample t-test; discrete variables were analysed using the w2 test. Repeated measures analysis of variance was used to analyse the trends of change of depression scores on HDRS and BDI. Analysis was done using the last observation carried forward method.

4. Results Table 1 shows the socio-demographic and clinical details of the sample. Both groups were comparable except that group-I had

Table 1 Socio-demographic and clinical details. Variables Mean age (SD) in years Mean duration of education (SD) in years Marital status [n(%)] Married Unmarried Employment Employed Unemployed Mean duration (SD) of current episode (in weeks) Mean haemoglobin (SD) level in gm% Mean of the mean corpuscular volume (SD; cubic microns) Recurrent depressive episodes [(n)%] Mean total baseline HDRS (SD) Mean total baseline BDI (SD)

Group-I (n ¼23) 31.7 (7.2) 4.70 (5.0) 15 (65.2) 8 (34.8) 20 3 9.9 12.87 90.0 7 21 25.1

(87.0) (13.0) (7.7) (0.6) (3.9) (30.4) (2.3) (5.2)

Group-II (n¼ 19)



34.6 (5.7) 6.6 (5.3)

 1.46  1.21

0.15 0.23





14 (73.7) 5 (26.3) 17 2 11.8 12.6 88.2 1 20.0 23.1

(89.5) (10.5) (8.7) (1.1) (4.6) (5.3) (1.4) (2.7)

 0.76 0.90 1.43 4.3 1.73 1.55

0.45 0.37 0.16 0.04 0.09 0.13


R. Venkatasubramanian et al. / Journal of Affective Disorders 150 (2013) 644–648

Total number of patients recruited for the trial (n=42)


GROUP 1 (n=23)

GROUP 2 (n=19)

(Fluoxetine 20mg + 1.5 mg folic acid)

(Fluoxetine 20mg + 5mg folic acid) Drop outs = 4

Drop outs = 8 Analysed using last observation carried forward method

Analysed using last observation carried forward method

Fig. 1. The CONSORT (Consolidated Standards of Reporting Trials) diagram showing the flow of participants through each stage of the trial.

Table 2 Decline in scores of Hamilton depression rating scale (HDRS). Day of evaluation

Group 1 mean (7 SD)

Group 2 mean (7 SD)

Day Day Day Day Day Day Day

21 20.6 19.3 18.5 17.6 16.5 15.9

19.9 19.5 18.6 17.5 15.3 13.1 11.5

0 7 14 21 28 35 42

(2.31) (2.63) (3.29) (4.28) (4.5) (5.72) (6.4)

(1.43) (1.54) (2.45) (2.75) (4.42) (5.56) (6.2)

Group I-1.5 mg folic acid/day. Group II-5 mg folic acid/day.

Table 3 Decline in scores of Beck Depression Inventory. Day of evaluation

Group 1 mean (7 SD)

Group 2 mean (7 SD)

Day Day Day Day Day Day Day

25.1 24.7 23.5 22.6 20.9 20.3 19

23.1 22.7 20.9 19 17.7 14.3 13.5

0 7 14 21 28 35 42

(5.16) (5.02) (5.59) (6.09) (7.17) (7.91) (8.95)

(2.66) (2.8) (3.68) (4.59) (4.84) (4.7) (6.71)

Fig. 2. Changes in the scores of Hamilton Depression Rating Scale during the 6 weeks of treatment course.

Group I—1.5 mg folic acid/day. Group II—5 mg folic acid/day.

significantly more number of previous episodes (p ¼0.04). Fig. 1 shows the flow of participants through each stage of the trial. Tables 2 and 3 show the changes in clinical status over 6 weeks as assessed using HDRS and BDI. respectively. Twelve patients dropped out at various stages as they were lost to follow up. The time X group interaction effect was significant suggesting greater improvement in group II patients with regard to scores on HDRS (Fig. 2) as well as BDI (Fig. 3). This result did not change even after controlling for the number of past episodes. As can be seen in Fig. 2, the time point of separation of response between the two groups was by the end of 3 weeks. With regard to Fig. 3, the time point of separation of response was by the end of 2 weeks. Effect sizes (Cohen’s d) were 0.7 for HDRS as well as BDI (Cohen, 1988). With regard to HDRS, seven (36.8%) group II patients remitted compared to two (8.7%) from group I

Fig. 3. Changes in the scores of Beck’s Depression Inventory during the 6 weeks of treatment course.

[w2 ¼4.9; p ¼0.03; number needed to treat (NNT)¼4]; nine patients (47.4%) of group II responded when compared to six (26.1%) from group I (w2 ¼2.0; p ¼0.15; NNT¼5). With regard

R. Venkatasubramanian et al. / Journal of Affective Disorders 150 (2013) 644–648

to BDI, five group II patients (26.3%) remitted when compared to two (8.7%) from group I (w2 ¼2.3; p ¼0.13); 10 patients (52.6%) from group II responded when compared to five (21.7%) from group I (w2 ¼ 4.3; p ¼0.04; NNT¼6). Five patients (26.3%) in group-II achieved remission on both scales compared to two (8.7%) from group-I (w2 ¼2.3; p ¼0.13). When remission to either of the scales was considered, the proportions were seven patients (36.8%) and two (8.7%; w2 ¼4.9; p¼ 0.03; NNT¼ 3) patients for group II and group I respectively. Proportion of patients who responded to either of the scales was 11 (57.9%) from group-II when compared to six (26.1%; w2 ¼4.37; p ¼0.04; NNT¼3) patients from group-I. Adverse effects were checked using a prepared checklist that included known adverse-effects of folic acid (including diarrhoea, abdominal cramps, sleep disorders, rash, confusion, nausea, seizures etc). None of the patients reported any adverse effects.

5. Discussion With the findings of our study, we can advocate that augmentation of 5 mg of folic acid/day with fluoxetine is more beneficial than augmentation with 1.5 mg folic acid/day in female patients suffering from depressive disorders. We recruited only female patients because there is evidence to suggest that the benefit of folic acid supplementation is more robust in females than in males (Coppen and Bailey, 2000). They also note that lack of response in men may be related to the smaller changes in plasma homocysteine in their study. In addition, they also raise the issue that men may require increasingly sufficient doses of folic acid to lower homocysteine levels thereby enhancing the antidepressant effect in men. Though we did not perform assays of folic acid or homocysteine, an exclusion criterion was a mean corpuscular volume of more than 100 fl in peripheral smear. This indirectly excluded patients with folic acid deficiency which manifests as macrocytic anaemia. This being the case, the results of our study are applicable only to patients without folic acid deficiency or those in whom folic acid deficiency is too little to produce changes in the mean corpuscular volume. Though the number of patients diagnosed to have recurrent depression were higher in group I, baseline HDRS and BDI were comparable across the two groups suggesting that this issue might not have influenced the results substantially. Moreover, the time X group interaction effect remained significant even after controlling for the number of past episodes. The aim of this study was to produce provisional guideline regarding optimal dosage for folic acid augmentation taking into consideration the ease of use of folic acid, cost and the policy of no harm to the patient. No adverse effects were noted in either group. We did not consider mega dosage of folic acid (e.g., 500 mg or so) because folic acid may increase the risk of cancer and also we do not know the dose gradient effect of folic acid with reference to its oncogenic effect. Though the carcinogenic dose of folic acid may be high, this concept is still controversial and more research is required to know the dose and the forms of folic acid which could have carcinogenic potential. Moreover, the long term effects of synthetic folic acid exposure (pteroylmonoglutamate) are not known with certainty (Lucock, 2004). At this stage, we cannot be sure that 5 mg of folic acid is not carcinogenic. However, it should also be noted that it may be unethical to withhold the benefit of folic acid in the absence of definite proof regarding its carcinogenic potential. Moreover, at the current point in time, the cancer risk appears theoretical. If the risks were substantial, pregnant women would not have been adviced folic acid supplementation. Mechanisms through which folic acid might help depression are as follows: (a) S-adenosyl methionine (SAM) which apart from


being an antidepressant itself, also increases serotonin turnover (Young, 2007); (b) Folic acid increases tetrahydrobiopterine (BH4) levels essential in the manufacture of neurotransmitters such as serotonin and dopamine from their corresponding amino acids (Gatof and Ahnen, 2002). We do not know how many of these mechanisms have a dose gradient relationship with folic acid. It will be enlightening to conduct further studies with multiple dosage regimens of folic acid in depressed patients along with their effect on serotonin, nor epinephrine and dopamine metabolism, so that we may know the precise suitable dosage for its augmenting effect.

6. Limitations Though this was not a placebo-controlled study, fluoxetine is a proven antidepressant. Hence this factor may not have affected the conclusion of the study (Dalery and Honig, 2003; Bennie et al., 1995; Chouinard et al., 1999; Fava et al., 2002). Another limitation may be that group I had significantly more number of patients with recurrent depressive disorder. This may remain as a limitation in spite of the similar cross-sectional scores at baseline, as recurrent depressions are harder to treat. Another is the issue of small sample size. The sample size was not calculated formally. Hence a possibility of a type-II error cannot be ruled out. Another limitation is that we cannot totally rule out recruitment bias. Since this was a hospital based study, it is possible that only patients with severe symptomatology come to hospitals. In this context, a recent review mentions that greater treatment refractoriness could contribute to patients’ recruitment into a clinical trial (Arfken and Balon, 2011).

Role of funding source No external funding was obtained for this study. The study was conducted as part of the MD dissertation and thesis allowance was provided (to the first author) by the institute (National Institute of Mental Health and Neurosciences, Bangalore, India).

Conflict of interest None declared for any of the authors.

Acknowledgements We thank Dr Subbakrishna and Mr Shanmugam who helped us with the statistical analyses; all the clinicians who helped us with the patient recruitment and finally all the participants who consented to be a part of this study.

References Abou-Saleh, M.T., Coppen, A., 2006. Folic acid and the treatment of depression. Journal of Psychosomatic Research 61, 285–287. Arfken, C.L., Balon, R., 2011. Declining participation in research studies. Psychotherapy and Psychosomatics 80, 325–328. Beck, A.T., Ward, C.T., Mendelson, M., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561–571. Bennie, E.H., Mullin, J.M., Martindale, J.J., 1995. A double-blind multicenter trial comparing sertraline and fluoxetine in outpatients with major depression. Journal of Clinical Psychiatry 56 (6), 229–237. Chouinard, G., Saxena, B., Be´langer, M.C., Ravindran, A., Bakish, D., Beauclair, L., Morris, P., Vasavan Nair, N.P., Manchanda, R., Reesal, R., Remick, R., O’Neill, M.C., 1999. A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder. Journal of Affective Disorders 54 (1–2), 39–48. Cohen, J., 1988. Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Lawrence Earlbaum Associates, Hillsdale, NJ. Coppen, A., Bailey, J., 2000. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo controlled trial. Journal of Affective Disorders 60, 121–130. Dalery, J., Honig, A., 2003. Fluvoxamine versus fluoxetine in major depressive episode: a double-blind randomised comparison. Human Psychopharmacology 18 (5), 379–384. Fava, M., Hoog, S.L., Judge, R.A., Kopp, J.B., Nilsson, M.E., Gonzales, J.S., 2002. Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive


R. Venkatasubramanian et al. / Journal of Affective Disorders 150 (2013) 644–648

disorder including effects of baseline insomnia. Journal of Clinical Psychopharmacology 22 (2), 137–147. Fava, M., Mischoulon, D., 2009. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. Journal of Clinical Psychiatry 70 (S5), 12–17. Gatof, D., Ahnen, D., 2002. Primary prevention of colorectal cancer: diet and drugs. Gastroenterology Clinics of North America 31, 587–623. Godfrey, P.S., Toone, B.K., Cawrney, M.W., Flynn, T.G., Bottiglieri, T., Laundy, M., 1990. Enhancement of recovery from psychiatric illness by methyl folate. Lancet 336, 392–395. Hamilton, M., 1960. Rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62. Keller, M.B., 2003. Past, present, and future directions for optimal treatment outcome in depression: remission and beyond. Journal of the American Medical Association 289, 3152–3160. Kelsey, J.E., 2002. Treatment strategies in achieving remission in major depressive disorder. Acta Psychiatrica Scandinavica 106 (Suppl. 415), 18–23. Lam, R.W., Kennedy, S.H., 2004. Evidence-based strategies for achieving and sustaining full remission in depression: focus on meta-analyses. Canadian Journal of Psychiatry 49 (Suppl. 1), 17S–26S. Lucock, M., 2004. Is folic acid the ultimate functional food component for disease prevention? BMJ 328, 211–214.

Passeri, M., Cucinotta, G., Abate, G., 1993. Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicentre study. Aging Clinical and Experimental Research 51, 63–71. Resler, G., Lavie, R., Campos, J., Mata, S., Urbina, M., Garcı´a, A., 2008. Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation 15, 145–152. Sarris, J., Kavanagh, D.J., Byrne, G., 2010. Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines. Journal of Psychiatric Research 44 (1), 32–41. Vergouwen, A.C., Burger, H., Koerselman, F., Verheij, T.J., 2007. Initial rate of improvement in relation to remission of major depressive disorder in primary care. Primary Care Companion—Journal of Clinical Psychiatry 9, 364–366. Willems, F.F., Boers, G.H., Blom, H.J., Aengevaeren, W.R., Verheugt, F.W., 2004. Pharmacokinetic study on the utilization of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. British Journal of Pharmacology 141, 825–830. World Health Organisation (WHO), 1992. International Statistical Classification of Diseases and Related Health Problems 10th Revision. WHO, Geneva, Switzerland. Young, S.N., 2007. Folate and depression—a neglected problem. Journal of Psychiatry Neuroscience 32, 80–82.