We have previously reported on the research by Martin Alda and colleagues that the chemical compound methylene blue had positive effects in patients with bipolar depression. The research was published in the British Journal of Psychiatry in 2016.
Now a new article by Ashley M. Feen and colleagues in the Journal of Neurotrauma reports that methylene blue has an antidepressant-like effect in mice with traumatic brain injury (TBI). Methylene blue reduced inflammation and microglia activation in the animals. Methylene blue reduced levels of the pro-inflammatory cytokine Il-1b and increased levels of the anti-inflammatory cytokine Il-10.
These findings are of particular interest as many patients with classical depression (and no brain injury) have abnormal levels of these inflammatory markers. It remains to be seen whether methylene blue is more helpful in those patients with elevated inflammatory markers and if levels of the markers can predict treatment response or not.
Methylene blue causes urine to turn blue, so low doses of the compound are used as a placebo. Alda and colleagues reported that the active dose 195mg reduced depression and anxiety significantly more than the placebo dose (15mg) in a 13-week crossover study. In that study, methylene blue was added to lamotrigine which had not had a complete enough effect.
In a 1986 study by G.J. Naylor and colleagues in the journal Biological Psychiatry, patients were treated with either 15mg/day or 300mg/day of methylene blue for one year and crossed over to the other dose in the second year. Participants had significantly less depression during the year of taking the active 300mg/day dose.
The FDA has issued a warning about the danger of a serotonin syndrome if methylene blue is combined with serotonin active agents (presumably because it inhibits MAO-A). Symptoms of the serotonin syndrome can include lethargy, confusion, delirium, agitation, aggression, decreased alertness, and coma. Neurological symptoms, such as jerky muscle contractions, loss of speech, muscle tension, and seizures; or autonomic symptoms, such as fever and elevated blood pressure, are also common. Patients should call their doctor if they are taking a serotonergic psychiatric medication and develop any of the above symptoms.
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
In a double-blind, placebo-controlled trial for patients with bipolar disorder, Martin Alda and colleagues from Dalhousie University in Halifax, Nova Scotia found that the compound methylene blue was an effective augmentation for mood stablizers. Methylene blue inhibits nitric oxide synthetase and guanylate cyclase, the overproduction of which might be associated with neuronal damage. Since bipolar disorder has consistently been associated with neuronal and glial cell dysfunction and loss, methylene blue could be a promising treatment.
Methylene blue turns urine blue, so in place of a placebo the researchers used very low doses (15 mg daily) of methylene blue compared with the active dose of 195 mgs daily.
Thirty-seven patients were enrolled in the randomized 26-week trial, and all patients were treated with lamotrigine as their primary mood stabilizer and with any additional medications they were already taking. Patients entered in a well or euthymic state (n =20), mildly depressed (n=14), or while minimally cycling (n = 3).
Scores on both the Montgomery-Asberg Depression Rating Scale and the Hamilton Rating Scale for Depression improved significantly, with an effect size of 0.47 and 0.42, respectively. Hamilton Anxiety Rating Scale scores also improved significantly with an effect size of 0.46.
Methylene blue was well tolerated, with only transient and mild side effects observed. However, the FDA has issued a warning that using methylene blue with serotonin active agents can lead to a severe serotonin syndrome (because methylene blue is a potent inhibitor of MAO-A and will increase brain serotonin levels when used in conjunction with serotonin active antidepressants). Symptoms of serotonin syndrome can include confusion, hyperactivity, sweating, fever, shivering, diarrhea, trouble with coordination, and even seizures.
The researchers at Dalhousie University concluded that methylene blue used as an adjunctive medication to lamotrigine and other previously inadequately effective agents (only those which are NOT serotonin active) significantly improved depression and anxiety in patients with bipolar disorder. They proposed further exploration of the mechanisms involved in this change, with the possibility that other drugs with similar actions could also be effective in this disorder.