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Folic acid and the treatment of depression
Journal of Psychosomatic Research 61 (2006) 285 – 287
Editorial
Folic acid and the treatment of depressionB Mohammed T. Abou-Saleha,4, Alec Coppenb a
St George’s Hospital, University of London, Crammer Terrace, London SW17 0RE, UK b MRC Neuropsychiatry Research Laboratory, Epsom, Surrey KT18 5JL, UK Received 20 June 2006
Abstract Reduced plasma, serum, or red blood cell folate is commonly found in major depressive illnesses. Supplementing antidepressant medication with folic acid enhances the therapeutic effect. Although more work is required to confirm these beneficial
results, it is suggested that, meanwhile, 2 mg of folic acid should be given during the acute, continuation, and maintenance treatment of depression. D 2006 Elsevier Inc. All rights reserved.
Keywords: Depression; Folic acid; Treatment; Vascular disease
Introduction Numerous studies have reported that patients with major depression have low plasma, serum, or red blood cell folate concentration [1]. We have previously found that both plasma and red blood cell folate concentrations were on average about 24% lower in drug-free, acutely ill depressed patients than in normal control subjects and that lower serum folate concentrations were associated with greater severity of depression [2]. An earlier study by Reynolds et al. [3] showed that the therapeutic outcome following antidepressant or electroconvulsive therapy was inferior if the plasma folate was low. High plasma folate levels are also important for the continuation treatment of depression. Papakostas et al. [4] followed up 71 outpatients with remitted major depression for 28 weeks who were treated with fluoxetine and found that the relapse rate of patients with low folate was 42.9% compared with the 3.2% relapse
B Declaration of interest: Alec Coppen possesses a patent for medication, including that for an antidepressant and folic acid, whereas Mohammed T. Abou-Saleh has none. 4 Corresponding author. St George’s Hospital, University of London, Crammer Terrace, London SW17 0RE, UK. E-mail addresses: [email protected] (M.T. Abou-Saleh)8 [email protected] (A. Coppen).
0022-3999/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2006.07.007
rate of patients with higher folate levels. Coppen and AbouSaleh [5] reported that patients with higher plasma folate attending a lithium clinic had significantly lower affective morbidity over 2 years than patients with lower plasma folate. Papakostas et al. [6] have also reported that, in patients who failed to respond to fluoxetine and who received augmentation therapy with lithium or desipramine, low folate was associated with a lower response rate (7.1%) than in those with normal folate levels (44.7%). Community studies have also shown a link between low serum folate and depressive symptoms. Sachdev et al. [7] examined the relationship between folic acid and depression in a community sample of 412 persons between 60 and 64 years of age and found that low serum folate and high homocysteine were associated with depressive symptoms. A further important finding is the association between coronary artery disease (CAD) and depression [8]. Surveys have shown that patients who develop depression have an increased risk of CAD and that patients with CAD who are depressed have a worse outlook than nondepressed patients. CAD and depression show a common pathology in the form of low serum folate [9]. Folate is a major determinant of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional
286
Editorial / Journal of Psychosomatic Research 61 (2006) 285 – 287
marker of folate deficiency, and increased homocysteine levels are found in depressive patients [10]. In a largepopulation study from Norway, increased plasma homocysteine was associated with increased risk of depression but not of anxiety [11]. Furthermore, the MTHFR C677T polymorphism that impairs homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association [12]. In folate-deficient depressed patients, CSF amine metabolites were significantly reduced in a subgroup of patients with high plasma homocysteine who also had the lowest levels of red blood cell and CSF folate and CSF SAM [13]. Implications for treatment It is important that the treatment of major depression, ranked by the WHO as the fourth most important cause of premature mortality and disability [14], is improved. Antidepressants are weak therapeutic agents and have not improved in efficacy since their introduction in the 1950s. Fifty percent of the patients responded to treatment using the active drug, whereas only 32% responded to placebo [15]. It is therefore crucial that we devise better treatments for this serious and lethal condition. Augmentation of antidepressants by folic acid Coppen and Bailey [15] reported a study of patients attending their general practitioners (GPs) with a major depressive disorder (DSM-III-R) and who scored at least 20 on the Hamilton Rating Scale (HRS). All GPs attended training sessions on the use of the DSM and the HRS. Among the eligible 127 patients, 109 completed the trial after random allocation to receive either 20 mg of fluoxetine plus 500 Ag of folic acid or fluoxetine with the placebo capsule. The trial was designed to last 10 weeks. Female patients receiving folic acid showed a significant increase in plasma folic acid and a 20% decrease in plasma homocysteine after 10 weeks. Men showed a much smaller increase of plasma folate after 10 weeks and showed no significant change in plasma homocysteine. Ninety-four percent of the women showed a therapeutic response on folic acid (N50% reduction in HRS score at the end of the trial), as compared with 61% of the women who received fluoxetine only. Men showed no improved clinical response, but their plasma folate levels increased by less than half of that of the women, and they showed no significant change in plasma homocysteine levels. A second small, double-blind trial by Godfrey et al. [16] was carried out on patients diagnosed with DSM-III major depression who have folate deficiency. Patients were rated on a clinical outcome scale. They were also allocated to receive either 15 mg of methylfolate or placebo. The patients receiving methylfolate showed a significant improvement after 3 and 6 months.
A recent Cochrane review has concluded that folate may have a potential role as a supplement to other treatments for depression. It is currently unclear if this is the case both for people with normal folate levels and for those with folate deficiency [17]. Further clinical trials in defined clinical subgroups are needed, but they should be long term (at least 3 months to 1 year), as the impact of folate is slow and cumulative over many months. Reynolds [18] has suggested, bthe best way forward may be to undertake large scale community based studies of folate supplementation or food fortification to explore the preventive potential of the vitamin for mood and cognitive disorders. Such studies are being designed or undertaken for the possible prophylaxis of vascular disease and could be adapted to address the question of preventing or reducing depression and dementia, including vascular dementia, while taking into account the special requirements of the nervous system.Q
Dosage of folic acid to augment antidepressants The study of Coppen and Bailey [15] showed that the dose of folic acid is important. For men, the 500-Ag dose of folic acid was insufficient to lower their plasma and homocysteine levels and to cause an improved response rate. We suggest the use of 2 mg of folic acid, which would be expected to increase plasma folate to more than 20 ng/ml in both sexes. Trials of antidepressant treatments take a long time to carry out, and continuation and maintenance studies take even longer. Adding 2 mg of folic acid to antidepressant treatment would be easy in everyday clinical practice. The daily supplement could be easily taken. It is inexpensive and safe. If the results of long-term trials were negative, then we would have done no harm, but if they were positive, then we would have saved a lot of lives and suffering.
References [1] Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 2005; 19:59 – 65. [2] Abou-Saleh MT, Coppen A. Serum and red blood cell folate in depression. Acta Psychiatr Scand 1989;80:78 – 82. [3] Reynolds EH, Preece JM, Bailey J, et al. Folate deficiency in depressive illness. Br J Psychiatry 1970;117:287 – 92. [4] Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder: Part 1 Predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004;65:1090 – 5. [5] Coppen A, Abou-Saleh MT. Plasma folate and affective morbidity during long-term lithium therapy. Br J Psychiatry 1982;141:87 – 9. [6] Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder: Part 2 Predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry 2004;65:1096 – 8.
Editorial / Journal of Psychosomatic Research 61 (2006) 285 – 287 [7] Sachdev PS, Parslow RA, Lux O, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 2005;35:529 – 38. [8] Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4 – 11. [9] Voutilainen S, Virtanen JK, Rissanen TH, et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2004; 80:317 – 23. [10] Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuro-Psychopharmacol Biol psychiatry 2005;29:1103 – 12. [11] Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677CYT polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003;60:618 – 26. [12] Kelly CB, McDonnell AP, Johnston TG, et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol 2004;18:567 – 71.
287
[13] Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436 – 42. [14] Agency for Health Care Policy and Research Treatment of Depression—New Pharmacotherapies. Summary. Evidence Report/ Technology Assessment: Number 7 http://www.ahrq.gov/clinic/ epcsums/deprsumm.htm. (1999). [15] Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 2000;60:121 – 30. [16] Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336: 392 – 5. [17] Taylor MJ, Carney SM, Goodwin GM, et al. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol 2004;18:251 – 6. [18] Reynolds EH. Folic acid, ageing, depression, and dementia. Br Med J 2002;324:1512 – 5.
Editorial
Folic acid and the treatment of depressionB Mohammed T. Abou-Saleha,4, Alec Coppenb a
St George’s Hospital, University of London, Crammer Terrace, London SW17 0RE, UK b MRC Neuropsychiatry Research Laboratory, Epsom, Surrey KT18 5JL, UK Received 20 June 2006
Abstract Reduced plasma, serum, or red blood cell folate is commonly found in major depressive illnesses. Supplementing antidepressant medication with folic acid enhances the therapeutic effect. Although more work is required to confirm these beneficial
results, it is suggested that, meanwhile, 2 mg of folic acid should be given during the acute, continuation, and maintenance treatment of depression. D 2006 Elsevier Inc. All rights reserved.
Keywords: Depression; Folic acid; Treatment; Vascular disease
Introduction Numerous studies have reported that patients with major depression have low plasma, serum, or red blood cell folate concentration [1]. We have previously found that both plasma and red blood cell folate concentrations were on average about 24% lower in drug-free, acutely ill depressed patients than in normal control subjects and that lower serum folate concentrations were associated with greater severity of depression [2]. An earlier study by Reynolds et al. [3] showed that the therapeutic outcome following antidepressant or electroconvulsive therapy was inferior if the plasma folate was low. High plasma folate levels are also important for the continuation treatment of depression. Papakostas et al. [4] followed up 71 outpatients with remitted major depression for 28 weeks who were treated with fluoxetine and found that the relapse rate of patients with low folate was 42.9% compared with the 3.2% relapse
B Declaration of interest: Alec Coppen possesses a patent for medication, including that for an antidepressant and folic acid, whereas Mohammed T. Abou-Saleh has none. 4 Corresponding author. St George’s Hospital, University of London, Crammer Terrace, London SW17 0RE, UK. E-mail addresses: [email protected] (M.T. Abou-Saleh)8 [email protected] (A. Coppen).
0022-3999/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2006.07.007
rate of patients with higher folate levels. Coppen and AbouSaleh [5] reported that patients with higher plasma folate attending a lithium clinic had significantly lower affective morbidity over 2 years than patients with lower plasma folate. Papakostas et al. [6] have also reported that, in patients who failed to respond to fluoxetine and who received augmentation therapy with lithium or desipramine, low folate was associated with a lower response rate (7.1%) than in those with normal folate levels (44.7%). Community studies have also shown a link between low serum folate and depressive symptoms. Sachdev et al. [7] examined the relationship between folic acid and depression in a community sample of 412 persons between 60 and 64 years of age and found that low serum folate and high homocysteine were associated with depressive symptoms. A further important finding is the association between coronary artery disease (CAD) and depression [8]. Surveys have shown that patients who develop depression have an increased risk of CAD and that patients with CAD who are depressed have a worse outlook than nondepressed patients. CAD and depression show a common pathology in the form of low serum folate [9]. Folate is a major determinant of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional
286
Editorial / Journal of Psychosomatic Research 61 (2006) 285 – 287
marker of folate deficiency, and increased homocysteine levels are found in depressive patients [10]. In a largepopulation study from Norway, increased plasma homocysteine was associated with increased risk of depression but not of anxiety [11]. Furthermore, the MTHFR C677T polymorphism that impairs homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association [12]. In folate-deficient depressed patients, CSF amine metabolites were significantly reduced in a subgroup of patients with high plasma homocysteine who also had the lowest levels of red blood cell and CSF folate and CSF SAM [13]. Implications for treatment It is important that the treatment of major depression, ranked by the WHO as the fourth most important cause of premature mortality and disability [14], is improved. Antidepressants are weak therapeutic agents and have not improved in efficacy since their introduction in the 1950s. Fifty percent of the patients responded to treatment using the active drug, whereas only 32% responded to placebo [15]. It is therefore crucial that we devise better treatments for this serious and lethal condition. Augmentation of antidepressants by folic acid Coppen and Bailey [15] reported a study of patients attending their general practitioners (GPs) with a major depressive disorder (DSM-III-R) and who scored at least 20 on the Hamilton Rating Scale (HRS). All GPs attended training sessions on the use of the DSM and the HRS. Among the eligible 127 patients, 109 completed the trial after random allocation to receive either 20 mg of fluoxetine plus 500 Ag of folic acid or fluoxetine with the placebo capsule. The trial was designed to last 10 weeks. Female patients receiving folic acid showed a significant increase in plasma folic acid and a 20% decrease in plasma homocysteine after 10 weeks. Men showed a much smaller increase of plasma folate after 10 weeks and showed no significant change in plasma homocysteine. Ninety-four percent of the women showed a therapeutic response on folic acid (N50% reduction in HRS score at the end of the trial), as compared with 61% of the women who received fluoxetine only. Men showed no improved clinical response, but their plasma folate levels increased by less than half of that of the women, and they showed no significant change in plasma homocysteine levels. A second small, double-blind trial by Godfrey et al. [16] was carried out on patients diagnosed with DSM-III major depression who have folate deficiency. Patients were rated on a clinical outcome scale. They were also allocated to receive either 15 mg of methylfolate or placebo. The patients receiving methylfolate showed a significant improvement after 3 and 6 months.
A recent Cochrane review has concluded that folate may have a potential role as a supplement to other treatments for depression. It is currently unclear if this is the case both for people with normal folate levels and for those with folate deficiency [17]. Further clinical trials in defined clinical subgroups are needed, but they should be long term (at least 3 months to 1 year), as the impact of folate is slow and cumulative over many months. Reynolds [18] has suggested, bthe best way forward may be to undertake large scale community based studies of folate supplementation or food fortification to explore the preventive potential of the vitamin for mood and cognitive disorders. Such studies are being designed or undertaken for the possible prophylaxis of vascular disease and could be adapted to address the question of preventing or reducing depression and dementia, including vascular dementia, while taking into account the special requirements of the nervous system.Q
Dosage of folic acid to augment antidepressants The study of Coppen and Bailey [15] showed that the dose of folic acid is important. For men, the 500-Ag dose of folic acid was insufficient to lower their plasma and homocysteine levels and to cause an improved response rate. We suggest the use of 2 mg of folic acid, which would be expected to increase plasma folate to more than 20 ng/ml in both sexes. Trials of antidepressant treatments take a long time to carry out, and continuation and maintenance studies take even longer. Adding 2 mg of folic acid to antidepressant treatment would be easy in everyday clinical practice. The daily supplement could be easily taken. It is inexpensive and safe. If the results of long-term trials were negative, then we would have done no harm, but if they were positive, then we would have saved a lot of lives and suffering.
References [1] Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol 2005; 19:59 – 65. [2] Abou-Saleh MT, Coppen A. Serum and red blood cell folate in depression. Acta Psychiatr Scand 1989;80:78 – 82. [3] Reynolds EH, Preece JM, Bailey J, et al. Folate deficiency in depressive illness. Br J Psychiatry 1970;117:287 – 92. [4] Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder: Part 1 Predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004;65:1090 – 5. [5] Coppen A, Abou-Saleh MT. Plasma folate and affective morbidity during long-term lithium therapy. Br J Psychiatry 1982;141:87 – 9. [6] Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder: Part 2 Predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry 2004;65:1096 – 8.
Editorial / Journal of Psychosomatic Research 61 (2006) 285 – 287 [7] Sachdev PS, Parslow RA, Lux O, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 2005;35:529 – 38. [8] Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry 1998;155:4 – 11. [9] Voutilainen S, Virtanen JK, Rissanen TH, et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2004; 80:317 – 23. [10] Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuro-Psychopharmacol Biol psychiatry 2005;29:1103 – 12. [11] Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677CYT polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003;60:618 – 26. [12] Kelly CB, McDonnell AP, Johnston TG, et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol 2004;18:567 – 71.
287
[13] Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349:1436 – 42. [14] Agency for Health Care Policy and Research Treatment of Depression—New Pharmacotherapies. Summary. Evidence Report/ Technology Assessment: Number 7 http://www.ahrq.gov/clinic/ epcsums/deprsumm.htm. (1999). [15] Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 2000;60:121 – 30. [16] Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336: 392 – 5. [17] Taylor MJ, Carney SM, Goodwin GM, et al. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol 2004;18:251 – 6. [18] Reynolds EH. Folic acid, ageing, depression, and dementia. Br Med J 2002;324:1512 – 5.