Key messages

• The addition of folate as augmentation in the treatment of major depressive disorder probably results in little or no difference in depressive symptoms at the end of treatment.

What is the evidence.
See evidence matrix  in Epistemonikos later

We found four systematic reviews [1],[2],[3],[4], which included nine primary studies overall [5],[6],[7],[8],[9],[10],[11],[12],[13], of which eight were randomized trials [6],[7],[8],[9],[10],[11],[12],[13]. This table and the summary in general are based on the latter, since the observational study did not increase the certainty of the existing evidence or provide relevant additional information.

What types of patients were included*

Six trials [6],[8],[9],[10],[12] included patients diagnosed with major depressive disorder according to DSM III or IV criteria, and two trials included patients with the same diagnosis according to ICD-10 [7],[13].

Of the eight trials selected, only one [9] exclusively included patients with low folate levels. On the contrary, two trials [6],[7] only included patients without baseline folate or B12 deficiency, and one trial [8] excluded patients with altered laboratory tests (including megaloblastic anemia). The rest of the trials [10],[12],[13] did not report this data.

What types of interventions were included*

All of the trials used selective serotonin reuptake inhibitors (SSRIs) as antidepressant, except two trials that did not report which antidepressant was used [7],[9].

Methylfolate was used as supplementation in three trials [9],[10] and folic acid in five trials [6],[7],[8],[12],[13].

Six trials compared against placebo [7],[8],[9],[10],[12], one trial compared against antidepressant monotherapy [6] and another trial compared different ranges of folate doses [13].

What types of outcomes
were measured

The trials measured multiple outcomes, which were grouped by the systematic reviews identified as follows:

• Improvement of depressive symptoms: Meassured with Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MADRS)
• Dropout rate
• Hospital admission
• Adverse effects
• Mortality.

To whom this evidence does and does not apply

• The conclusions of this summary are applicable to adult patients diagnosed with major depressive disorder.
• The objective of this article was to include any type of folate (folic acid or methylfolate) in any population (with or without folate deficiency). It would be interesting to explore the effects of folate augmentation in population with objective deficit, its role associated with other B-complex nutraceuticals and the specific effects of methylfolate.

• The outcomes selected are those considered critical for decision-making by the authors of this summary. In general, they coincide with those reported by the identified reviews.
• Although only one trial [8] presented data about adverse effects suitable to estimate an effect measure, the other seven trials [6],[7],[9],[10],[12],[13] were in agreement with the first, reporting folate was generally well tolerated, with gastrointestinal symptoms (constipation, abdominal discomfort and diarrhea) being the most commonly reported.
• Only one trial reported hospitalization rate with a single event in the placebo group.

• Folate would be an intervention probably ineffective, but without adverse effects in comparison to placebo.
• One systematic review [3] emphasizes there might be adverse effects when used in high doses, prolonged periods of time or in combination with certain medications. Possible carcinogenic, neurological and haematological effects are highlighted.
• Folic acid has also been implicated in the acceleration of age-related cognitive deterioration and reduction of the effect of certain antifolate drugs such as immunosuppressants [3].
• It should be taken into account that in the context of a deficit of B12, the addition of folate can have harmful consequences at a neurological and hematological level [2].

• Folate is generally a low-cost intervention, so this factor should not play an important role in decision-making.

• The use of nutraceuticals in psychiatry corresponds to a relatively emerging field. Over the past two decades and fostered by both experimental and epidemiological studies [2], the influence of nutritional factors has experienced increasing attention by the scientific community.
• On the other hand, the interest for alternative treatments versus traditional medicine has grown in the general population, and studies have suggested higher willingness-to-pay for them and higher placebo effect properties [14],[15],[16]. Therefore, it is relevant for mental health professionals to be aware of the best available evidence in this area.
• Regarding folate, most patients and physicians should lean against the intervention based on the information presented in this summary.

Differences between this summary and other sources

• In two systematic reviews [1],[4], concluded the available evidence suggested folate could have a potential role as an augmentation treatment, but it was not clear if this applied to both people with normal and low levels of folate. In addition, they remarked the eventual appearance of one or two relatively small trials with neutral or negative results could have a substantial impact on the estimate.
• In the most current systematic reviews [2],[3], which include more studies and more recent, the authors conclude there is a non-significant difference between folic acid and placebo. In relation to methylfolate in particular, they estimate there is too little evidence to reach firm conclusions yet. They mention it could be tentatively recommended, but they also note that although trials had a sound methodology, there might be bias towards positive results since they are funded by industry.
• Regarding the main clinical guidelines, both the 2010 American Psychiatric Association's (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder [17] and the 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder of the Canadian Network for Mood and Anxiety Treatments (CANMAT) [18] agree on the recommendation for the use of folate. On one hand, the APA considers there is modest evidence to recommend the addition of folate, but it is a low-risk intervention with general health benefits. On the other hand, CANMAT recommends folate augmentation as a third-line alternative for mild to moderate major depressive disorder. It should be noted that the guideline Depression in adults: recognition and management guide of the National Institute for Health and Care Excellence (NICE) [19] does not mention folate or other nutraceuticals as alternatives for enhancement, indicating the possibilities of using lithium, antipsychotics such as quetiapine or other antidepressants such as mirtazapine

• The likelihood that the information provided in this summary changes with future evidence is low, since the investigation provides a good indication of the likely effect.
• More evidence is needed to assess if there are benefits in populations with folate deficiency, or with the use of methylfolate.
• We identified at least one ongoing systematic review [20] in PROSPERO and at least five ongoing trials [21],[22],[23],[24],[25] in the International Clinical Trials Registry Platform of the World Health Organization, which could provide relevant information in the future.