Folate Abstracts 10

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Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies.
            (Botez et al., 1977) Download
Two groups of patients with folic acid responsive neurological and psychiatric disorders are reported. The first group (7 patients) had well-established acquired folate deficiency due either to defective absorption (4 cases with atrophy of jejunal mucosa) or to a deficient diet (3 cases). One patient had a subacute combined degeneration of the spinal cord while others were depressed and had weight loss, permanent muscular and intellectual fatigue, restless legs syndrome, depressed ankle jerks, diminution of the sense of vibration in the knees and a stocking-type tactile hypoesthesia. The second group (9 patients) comprised idiopathic cases of folic acid deficiency. Their main subjective complaints were chronic fatigability and familial restless legs syndrome. The neurological findings were similar to those of the patients with acquired disorders. Neuropsychological testing procedures revealed an abnormal intellectual functioning in all 16 patients. Abnormal patterns of radionuclide cisternograms and computerized transaxial tomography (CTT) were found in 11 patients. After 6-12 months of folic acid therapy a striking improvement regarding their intellectual functioning was noticed: the IQ, Kohs Block Design and Category tests were significantly improved. The correlation of neuropsychological findings with CTT and radionuclide cisternograms led to the conclusion that chronic folate deficiency could induce cerebral atrophy.

A pilot study of vitamin B12 in the treatment of tiredness.
            (Ellis and Nasser, 1973) Download
Twenty-eight subjects complaining of tiredness completed a double-blind cross-over trial of injections of hydroxocobalamin (jmg twice weekly for z weelts) followed by a rest period of 2 weeks and then a similar course of matching placebo injections. Symptoms werc assessed by a daily self-rating method and included appetite, mood, energy, sleep and general feeling of well-being. Those subjects who received the placebo in the first a-week period showed a favourable response to hydroxocobalamin in the second period in all measurements made. The response achieved statistical significance ( P = 0.006) in respect of general well-being; ' happiness' achieved a value of P = 0.032. Subjects who received hydroxocobalamin in the first period showed no difference between responses to active and placebo treatments, which suggests that the effects of the vitamin may persist for a period of at least 4 weeks.

Enhancement of recovery from psychiatric illness by methylfolate.
            (Godfrey et al., 1990) Download
41 (33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major depression or schizophrenia) had borderline or definite folate deficiency (red-cell folate below 200 micrograms/l) and took part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic treatment. Among both depressed and schizophrenic patients methylfolate significantly improved clinical and social recovery. The differences in outcome scores between methylfolate and placebo groups became greater with time. These findings add to the evidence implicating disturbances of methylation in the nervous system in the biology of some forms of mental illness.

Enhancement of recovery from psychiatric illness by methylfolate.
            (Godfrey et al., 1992) Download
Anderson et al and Wing & Lee have some reservations about some aspects of the design of our trial, while at the same time stressing the importance of the folate mental disorder connection and drawing attention to their own interesting contributions to the subject.

An open trial of methyltetrahydrofolate in elderly depressed patients.
            (Guaraldi et al., 1993) Download
5-methyltetrahydrofolate (MTHF) is a naturally occurring substance involved in the synthesis of s-adenosyl-l-methionine (SAMe), a major source of methyl groups in the brain. To assess the efficacy of a gastro-resistant, oral preparation of MTHF, 20 elderly patients with a DSM-III-R diagnosis of depressive disorder and a HAM-D-21 score > or = 18 underwent 6-weeks of open-label treatment with 50 mg per day of oral MTHF. Of these 20 patients, 16 completed at least 4 weeks of treatment and showed a markedly significant improvement in their depressive symptoms at endpoint, with 81% of them being considered responders. There were no clinically relevant changes in the routine laboratory tests during the study, and no adverse events considered to be definitely drug-related were reported.

Clinical activity of folinic acid in patients with chronic fatigue syndrome.
            (Lundell et al., 2006) Download
A high incidence of severe B-cell immunodeficiency and chronic reactivated Epstein-Barr virus (EBV) infection in patients with chronic fatigue syndrome (CFS) is reported herein. Of the 58 patients evaluated, 100% had evidence of prior EBV exposure and 72% had evidence for reactivated EBV infection. Notably, 94% of CFS patients had B-cell immunodeficiency with a marked depletion of their CD19+IgM+ mature B-lymphocyte population. A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid (CAS 58-05-9, leucovorin). The findings provide unprecedented evidence that CFS frequently is a folinic acid responsive clinical entity accompanied by B-cell immunodeficiency and inappropriate antibody responses to EBV.

L-Methylfolate For Bipolar I depressive episodes: An open trial proof-of-concept registry.
            (Nierenberg et al., 2017) Download
BACKGROUND:  L-methylfolate is a compelling candidate to treat bipolar I major depressive episodes. While approved as an adjunct for unipolar major depressive disorder, no studies have been done to assess the tolerability, safety, and efficacy of L-methylfolate for bipolar depression. As a first step, we developed a registry of bipolar patients treated with L-methylfolate to examine tolerability and outcomes. METHODS:  Subjects (N=10) received treatment as usual plus daily L-methylfolate 15mg for 6 weeks in this open-label registry. Depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and manic symptoms with the Young Mania Rating Scale (YMRS). Effect size was measured with Cohen's d to provide an estimate of potential efficacy. RESULTS:  The pre-treatment mean (SD) MADRS score was 23.4 (4.34); the post-treatment score was 13.9 (8.24). Cohen's d was 1.19. At post-treatment, 6/10 patients had at least 50% MADRS improvement, and 4/10 patients exhibited remission with MADRS≤10. The pre-treatment YMRS score was 3.2 (3.0); the post-treatment score was 2.7 (5.2). Cohen's d was 0.17. LIMITATIONS:  This registry was a small open-label clinical trial for a fluctuating disorder. We cannot rule out that our results are due to regression to the mean. A controlled trial is warranted. CONCLUSIONS:  This first proof-of-concept open registry suggests that L-methylfolate in combination with treatment as usual has potential to treat bipolar depression.

Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.
            (Papakostas et al., 2014) Download
OBJECTIVE:  Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). METHOD:  The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011. RESULTS:  Seventy-five patients were enrolled. Patients with specific biological (body mass index ≥ 30 kg/m², elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo. CONCLUSIONS:  Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed. TRIAL REGISTRATION:  ClinicalTrials.gov identifier: NCT00955955.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.
            (Papakostas et al., 2012) Download
OBJECTIVE:  The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD:  In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS:  In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS:  Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study.
            (Passeri et al., 1993) Download
5'-Methyltetrahydrofolic acid (5'-MTHF) in addition to standard psychotropic medication significantly improved clinical recovery in depressed patients with borderline or definite folate deficiency, and significantly reduced depressive symptoms in elderly normofolatemic patients after 3 weeks of treatment. In this equivalence study the effect of 5'-MTHF on depressive symptoms and cognitive status was compared to Trazodone (TRZ) in normofolatemic elderly patients with mild to moderate dementia and depression. Ninety-six patients with dementia, scoring 12-23 at the Mini Mental State Examination (MMSE) and > or = 18 at the Hamilton Depression Rating Scale (HDRS) after a 2-week placebo run-in, were randomized to receive either 5'-MTHF (50 mg/day p.o.) (47 patients) or TRZ (100 mg/day p.o.) (49 patients) in a double-blind design for 8 weeks. HDRS was assessed before, after 4 weeks and at the end of treatment; Rey's Verbal Memory (RVM) test for immediate and delayed recall was evaluated before and after treatment. After 4 weeks of treatment HDRS score was reduced from 23 +/- 5 to 20 +/- 6 in the 5'-MTHF (p < 0.05 vs baseline), and from 23 +/- 3 to 21 +/- 4 in the TRZ group (p < 0.05 vs baseline). A further significant decrease to 18 +/- 6 and 19 +/- 5 respectively was obtained at the end of the treatment period (p < 0.05 vs week 4) with 5'-MTHF and TRZ.(ABSTRACT TRUNCATED AT 250 WORDS) (Passeri et al., 1993)

Enhancement of recovery from psychiatric illness by methylfolate.
            (Procter, 1991) Download
41 (33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major depression or schizophrenia) had borderline or definite folate deficiency (red-cell folate below 200 micrograms/l) and took part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic treatment. Among both depressed and schizophrenic patients methylfolate significantly improved clinical and social recovery. The differences in outcome scores between methylfolate and placebo groups became greater with time. These findings add to the evidence implicating disturbances of methylation in the nervous system in the biology of some forms of mental illness."

Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study.
            (Zajecka et al., 2016) Download
OBJECTIVE:  To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg. METHOD:  Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks. Subjects were enrolled between September 2006 and February 2010. Efficacy outcomes included predefined criteria for response, remission, recovery, relapse, and recurrence. Subjects treated with adjunctive L-methylfolate 15 mg were included in the efficacy analysis. RESULTS:  Of 68 subjects who met criteria for the 12-month open-label phase, 38% (n = 26) achieved full recovery, and none experienced a recurrence of MDD. For subjects entering the open-label phase in remission (n = 11), 91% (n = 10) achieved full recovery with L-methylfolate 15 mg, and none experienced a relapse or recurrence. Among 57 subjects who entered the open-label phase as nonremitted, 61% (n = 35) achieved remission. Of subjects who entered the open-label phase with a response without remission (n = 4), 50% (n = 2) had full recovery, and of subjects entering the open-label phase with no response (n = 53), 26% (n = 14) met recovery criteria. CONCLUSIONS:  Adjunctive L-methylfolate 15 mg/d may be an early option in patients who fail to adequately respond to antidepressant monotherapy, with preliminary evidence demonstrating sustained remission and sustained recovery. TRIAL REGISTRATION:  ClinicalTrials.gov identifier: NCT00321152.

 


References

Botez, MI, et al. (1977), ‘Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies.’, Eur Neurol, 16 (1-6), 230-46. PubMed: 615714
Ellis, FR and S Nasser (1973), ‘A pilot study of vitamin B12 in the treatment of tiredness.’, Br J Nutr, 30 (2), 277-83. PubMed: 4583554
Godfrey, P, et al. (1992), ‘Enhancement of recovery from psychiatric illness by methylfolate.’, Br J Psychiatry, 161 126-27. PubMed: 1638313
Godfrey, PS, et al. (1990), ‘Enhancement of recovery from psychiatric illness by methylfolate.’, Lancet, 336 (8712), 392-95. PubMed: 1974941
Guaraldi, GP, et al. (1993), ‘An open trial of methyltetrahydrofolate in elderly depressed patients.’, Ann Clin Psychiatry, 5 (2), 101-5. PubMed: 8348200
Lundell, K, et al. (2006), ‘Clinical activity of folinic acid in patients with chronic fatigue syndrome.’, Arzneimittelforschung, 56 (6), 399-404. PubMed: 16889122
Nierenberg, AA, et al. (2017), ‘L-Methylfolate For Bipolar I depressive episodes: An open trial proof-of-concept registry.’, J Affect Disord, 207 429-33. PubMed: 27794238
Papakostas, GI, et al. (2012), ‘L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.’, Am J Psychiatry, 169 (12), 1267-74. PubMed: 23212058
Papakostas, GI, et al. (2014), ‘Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial.’, J Clin Psychiatry, 75 (8), 855-63. PubMed: 24813065
Passeri, M, et al. (1993), ‘Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study.’, Aging (Milano), 5 (1), 63-71. PubMed: 8257478
Procter, A (1991), ‘Enhancement of recovery from psychiatric illness by methylfolate.’, Br J Psychiatry, 159 271-72. PubMed: 1773245
Zajecka, JM, et al. (2016), ‘Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study.’, J Clin Psychiatry, 77 (5), 654-60. PubMed: 27035404