levoleucovorin and Depressive-Disorder--Major

The use of two antidepressants from the initiation of treatment in major depressive disorder has been investigated in several recent studies and forms a paradigm shift in the pharmacotherapy of the condition. Several, but not all, trials have claimed improved response and remission rates with the combinations as opposed to monotherapy. The use of folate preparations (folic and folinic acid and l-meth-ylfolate) have shown effective augmentation of antidepressant response in a variety of controlled and open-label settings in patients with normo- and hypofolatemic status. Several recent trials using L-methylfolate, the active and more bioavailable form of folic acid, have shown promising adjunctive use with a well-tolerated adverse event profile.

Topics: Antidepressive Agents; Depressive Disorder, Major; Drug Therapy, Combination; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Tetrahydrofolates; Treatment Outcome

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and L-methylfolate), and folinic acid. Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B(12) deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks. Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.

Topics: Aged; Chemistry, Pharmaceutical; Clinical Trials as Topic; Dementia; Depressive Disorder, Major; Dietary Supplements; Dosage Forms; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Tetrahydrofolates; Treatment Outcome

Low folate is associated with poorer response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). Folate supplementation in MDD has been studied in other settings with promising results. The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI. Twenty-two adults (59% female; mean age 45.2 +/- 11.0 years) with DSM-IV MDD, partial or nonresponse to an SSRI after at least 4 weeks of treatment, and a 17-item Hamilton Depression Rating Scale (HAM-D-17) score > or = 12 were enrolled in this 8-week prospective open trial. Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI, or B12 deficiency. Leucovorin (folinic acid), which is metabolized to methylfolate, was added to SSRIs at 15-30 mg/day. Folate levels rose from 28 +/- 19 ng/mL to 301 +/- 203 ng/mL (p < 0.001). HAM-D-17 scores among the 16 completers decreased from 19.1 +/- 3.9 to 12.8 +/- 7.0 (p < 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) sample achieved response (> or = 50% reduction in HAM-D-17 scores), and only 19% of completers and 18% of the ITT sample achieved remission (HAM-D-17 < or = 7). Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels. The application of leucovorin as an adjunct in the setting of refractory depression deserves further study.

Topics: Adult; Aged; Depressive Disorder, Major; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Middle Aged; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Treatment Outcome