95
significantly related to treatment response. Thus, without supplementation, low folate
appeared to inhibit people’s response to SSRIs.
This result was replicated in the 2005 Papacostas et al. study which linked the timing
of lithium and SSRI treatment effectiveness and the risk of relapse to low
pretreatment folate levels, using fluoxetine, lithium, and desipramine (Norpramin).^8
The seven subjects with low folate levels had a 43% relapse rate, compared to 3% for
the 64 with normal folate levels. Conversely, when people with folate deficiencies
received supplementation with methylfolate to counteract low folate levels, a small
1990 study showed an improved treatment response. This study was criticized because
the non-CAM treatments were diverse and not comparable.^9
In the 2002 Alpert et al. open label study in which Mischoulon participated, adjunctive
use of folinic acid with an SSRI produced more than 50% improvement in more than
25% of the subjects.^10 No individuals in this group were folate-deficient. The dose was
15 - 30 mg per day of folinic acid, which is metabolized to methylfolate. Of 22 subjects
who had minimally responded to 4 weeks of SSRI treatment prior to folate
supplementation, 33% improved, and 19% achieved full remission. The effect was not
limited to women.
A 2009 Fava and Mischoulon review^11 yielded firmer conclusions: “The methylfolate
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.” The noted effects were not limited to
women.
In Brown et al. II, Bottiglieri analyses the six randomized studies that have focused on
folate supplementation for depression, all but one of which has been adjunctive with
use of lithium or SSRIs. He concludes that they show promise, even in the absence of
folate deficiency. He also cites the 2012 series of trials conducted by Papacostos et al.
(and still not posted on PubMed) that “support the use of methylfolate as an