ClinicalTrials.gov identifier: NCT00955955.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.

Depression is a prevalent psychiatric disorder associated with significant personal and societal burden. There is accumulating evidence for the presence of a subtype of depression characterized by the presence of irritability that is associated with increased morbidity, risk for suicidal ideation, and functional impairments in adults. Little is known about the features of depressive symptoms with and without irritability among young adults in college. The primary aim of this study was to characterize the presentation of college students with depressive symptoms and irritability. Two-hundred eighty-seven undergraduate college students with depressive symptoms with and without irritability were compared across several psychiatric and functional outcome variables. Independent samples t-tests or logistic regressions were conducted for each outcome variable using the irritability item of the Beck Depression Inventory as a dichotomous grouping variable. Analyses were conducted separately for the men and the women. Both male and female students with depressive symptoms and severe irritability reported a greater severity of depressive symptoms compared with their peers with no or mild irritability. In the women, the presence of irritability was associated with greater symptoms of anxiety, whereas in the men, it was associated with increased likelihood of engaging in risky behaviors, including compulsive use of alcohol, illicit drugs, and prescription drugs. The male and female college students with depressive symptoms with and without irritability did not differ on severity of suicidal ideation, hopelessness, or cognitive functioning. The findings from this study suggest that depressive symptoms and irritability may characterize a subtype of college students who have a greater symptom burden and with the potential need for more aggressive and prompt treatment.

We have recently examined the efficacy of low-dose aripiprazole augmentation for major depressive disorder (MDD), with modest nonsignificant benefit found. In a secondary investigation, we examined whether aripiprazole resulted in improvement in four subscales (depression, anxiety, somatic symptoms, and hostility) of the Kellner Symptom Questionnaire (KSQ). We reanalyzed data from the main outcome study on 221 MDD patients with inadequate response to selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. Patients were randomized, using the sequential parallel comparison design, into two 30-day phases, as follows: drug/drug (aripiprazole 2 mg/day in phase 1, aripiprazole 5 mg/day in phase 2), placebo/drug (placebo in phase 1, aripiprazole 2 mg/day in phase 2), or placebo/placebo (placebo in both phases). We examined changes in the KSQ score from baseline to endpoint on the basis of the subscaled Well-being and Reversal Distressed Anxiety Subscales. The score for the KSQ depression subscale improved from baseline to the end of follow-up, with a significant advantage for aripiprazole over placebo (P=0.0327). Although improvement was also observed in the anxiety and hostility scales, neither attained a significant advantage over placebo; no significant change was observed for the somatization subscale. Aripiprazole augmentation resulted in a significant improvement compared with placebo augmentation only in the depression subscale of the KSQ; however, the low dose may not have been enough to have an impact on the anxiety and hostility scales. The good tolerability of the low dose may have resulted in the absence of worsening of somatic symptoms. Prospective studies are needed to better characterize the impact of low doses of aripiprazole augmentation on different manifestations of MDD.