Case Vignette 2
“Leslie” was a 43-year-old married white woman who presented with a history of treatment-resistant MDD with multiple antidepressant failures. The trials included imipramine, paroxetine, sertraline, escitalopram, duloxetine, venlafaxine, and fluoxetine. Her medical history was significant for multiple sclerosis, asthma, and migraines. She was taking venlafaxine XR 225 mg for an adequate duration, but there was a suboptimal response of her depressive symptoms when the 15 mg L-methylfolate daily was added. Upon follow up six weeks later, she reported that her experience with the L-methylfolate was horrible, describing herself as feeling “agitated and aggressive.”
Case Vignette 3
“Susan” was a 56-year-old divorced white mother with a longstanding history of bipolar disorder who presented with an episode of depression. She had had previous episodes of mania, complicated mania with psychosis, and depression as well as several inpatient psychiatric hospitalizations for repeated manic episodes and psychotic symptoms; her most recent hospitalization was more than 15 years prior to the current episode of depression. Over the previous several years, her symptoms were reasonably well-managed on a combination of carbamazepine and oral/depo injection haloperidol. Chronic residual symptoms included a notably flat affect, anhedonia, and a largely depressed mood at baseline.
Pharmacogenomic testing was performed as part of her work up, and it revealed that her MTHFR gene tested homozygous (T677T), which suggested poor enzymic activity. A trial of 15 mg L-methylfolate daily was initiated to target recalcitrant depressive symptoms.
The patient called a few days after L-methylfolate initiation and described feeling unwell, agitated, and seeming to be a bit paranoid. She was instructed to discontinue the L-methylfolate, and these symptoms resolved within a few days. She reported that she quickly felt more like herself after discontinuing the L-methylfolate. She described the brief trial as horrible and stated that she “will never take it (L-methylfolate) again.”
These case vignettes suggest that patients with unipolar or bipolar depression may be at risk for the onset of agitation shortly after beginning a trial of 15 mg L-methylfolate. In all three cases, the agitation resolved a few days after discontinuing the L-methylfolate, supporting the likelihood that it contributed to the agitation. It is interesting to note that the two patients with MDD both had a comorbid diagnosis of multiple sclerosis. This, however, may very well be coincidental.
The findings presented are preliminary and are presented with the aim of raising clinicians’ awareness that L-methylfolate may contribute to symptoms of agitation, irritability, and possibly hypomania, mixed mania, or mania in susceptible individuals. The only concrete conclusion that can be drawn is that well-designed clinical trials are needed to ferret out the rare but potentially significant adverse events associated with L-methylfolate.
There are no clinical data on the risks/benefits/adverse effects of the use of L-methylfolate off label in the treatment of bipolar depression. This is a significant lack of information, because many patients who ultimately have a diagnosis of bipolar disorder are initially treated—sometimes for years and even decades—for unipolar depression. The study by Papakostas and colleagues6 demonstrated that 7.5 mg of L-methylfolate performed no better than placebo as an augmentation agent in patients with MDD who did not respond to SSRIs, whereas 15 mg per day of L-methylfolate significantly separated from placebo. The dose response of L-methylfolate for effectiveness and adverse events in BD-I is unknown.
Future studies to assess the clinical consequences of augmenting antidepressants with L-methylfolate should include:
1. Large placebo controlled clinical trials of both unipolar depression and bipolar depression to determine the number needed to harm in the different patient populations, as well as the number needed to treat in bipolar patients.
2. Augmentation of non-SSRI antidepressants with L-methylfolate to determine if the improvement seen in MDD when SSRIs are augmented with L-methylfolate are generalizable to all antidepressants.
3. An evaluation of the L-methylfolate dosage range in patients with bipolar depression to determine which dosages (3.75 mg, 7.5 mg, 15 mg) are helpful and which are harmful.
These three cases illustrate the rare but possible adverse effects of agitation, irritability and possible onset of hypomania with adjunctive L-methylfolate. The publications reviewed report one patient who developed manic symptoms while taking L-methylfolate/SSRI for unipolar depression,6 and one patient who developed an increase in the YMRS and a possible manic episode when L-methylfolate was added to the regimen treating the underlying bipolar disorder.8 This activation by L-methylfolate is consistent with its putative mechanism of action, specifically increasing brain levels of norepinephrine, dopamine, and serotonin.
L-methylfolate, the bioactive form of folate that crosses the blood-brain barrier, has been shown to effectively augment SSRIs in patients with MDD who did not respond to SSRI monotherapy; and it also has been shown to be generally well tolerated. Its role in augmentation in bipolar depression remains to be determined. Although the current data are limited, clinicians and patients should be aware of the possibility that L-methylfolate may increase agitation and may contribute to the onset of hypomania/mania.
Ms Robinson is Psychiatric-Mental Health Nurse Practitioner, Seacoast Mental Health Center, Portsmouth, NH; and Clinical Assistant Professor, Department of Nursing, University of New Hampshire, Durham, NH; Dr Miller is Medical Director, Brain Health, Exeter, NH; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; and Consulting Psychiatrist, Insight Meditation Society, Barre, MA. Ms. Robinson and Dr Miller indicate they have nothing to disclose regarding the subject of this article.
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