Jill Stein

September 06, 2011

September 6, 2011 (Paris, France) — The compound methylene blue, which has a variety of uses, markedly reduces residual symptoms of depression and mania in patients with bipolar disorder, according to results of a phase 3 study released here at the 24th Congress of the European College of Neuropsychopharmacology.

However, the data from the 26-week study also show that the oral agent only slightly improves cognitive symptoms.

Dr. Martin Alda

"Residual symptoms of depression and anxiety occur in more than half of patients undergoing treatment for bipolar disorder, and they are often the main reason that patients can't return to full functioning," Martin Alda, MD, professor and Killam Chair, Department of Psychiatry, Dalhousie University in Halifax, Nova Scotia, Canada, told Medscape Medical News.

"Commonly used approaches for managing residual symptoms, which typically involve optimizing mood stabilizers — like lithium, carbamazepine, atypical antipsychotics, and lamotrigine — may be helpful to the point that patients no longer have profound depression or severe mania; however, they are still not quite able to function at 100%."

"While there is no specific treatment approved for the management of residual symptoms in bipolar patients, there are even fewer options for cognitive dysfunction, which is present in a majority of patients with bipolar disorder," he added. "Different things have been tried, including cognitive rehabilitation, intranasal insulin, and N-acetylcysteine, but nothing has been shown to be fully effective and nothing is used in clinical practice."

Dr. Alda was quick to emphasize that about a third of patients with bipolar disorder will improve significantly with the mood stabilizer lithium given as monotherapy and do not have residual symptoms or cognitive dysfunction. The analysis excluded such patients.

Methylene Blue Study Protocol

Methylene blue is primarily used to treat carbon monoxide poisoning, but it is also used as a dye to enhance visualization of tissues during surgery. Several clinical studies of bipolar disorder have reported favorable effects on mood with the compound.

Dr. Alda and his team hypothesized that methylene blue would improve residual symptoms in bipolar patients because of a possible neuroprotective effect mediated by the inhibition of nitric oxide synthase and guanylate cyclase.

The study comprised 37 men and women 18 to 65 years of age who satisfied both research diagnostic criteria and Diagnostic and Statistical Manual, fourth edition (DSM IV) criteria for bipolar I disorder.

At baseline, 20 patients were euthymic, 14 patients were mildly depressed, and 3 patients were mildly cycling.

Patients were randomized to 13 weeks of treatment or either low-dose methylene blue (15 mg daily), which was a surrogate for placebo, or high-dose methylene blue (195 mg daily), and then switched to the alternate treatment for the next 13 weeks. Because methylene blue stains urine, it was not possible to use a standard placebo.

All participants were treated with lamotrigine as their primary mood stabilizer; additional medications were allowed, provided they remained constant throughout the trial.

Improvements Observed With Methylene Blue

The Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 11.1 ± 7.7, the Hamilton Rating Scale for Depression (HAMD) score was 5.5 ± 5.0, the Young Mania Rating Scale score was 2.8 ± 3.2, and the Hamilton Anxiety Scale (HAMA) score was 7.4 ± 4.6.

"Our main finding was that the active dose of methylene blue was very effective for residual problems, with patients feeling better subjectively and on objective measures, including the rating scales for anxiety and depression," Dr. Alda said.

Compared with the placebo dose, the active dose of methylene blue improved symptoms of depression on the MADRS and HAMD scales by 6.6 ± 14.2 and 4.1 ± 10.0 points, respectively (effect sizes, 0.47 and 0.42, respectively; P = 0.02 and 0.03, respectively).

In addition, patients on the active dose reported an improvement in anxiety on the HAMA scale by 4.1 ± 9.0 points (effect size, 0.46; P = .004). Ratings of mania remained low and constant throughout the study.

The effect of methylene blue on cognitive symptoms, like verbal memory, was weak and only marginally significant. Importantly, the compound did not worsen any of the cognitive symptoms.

"While the results were less striking on verbal memory, we don't know whether 13 weeks is really long enough to improve neuropsychological functioning, which could be measured statistically but did not have a huge effect on overall functioning," Dr. Alda said.

The medication was well tolerated, with only transient adverse effects, such as nausea.

Although 10 patients withdrew from the study, mostly because they disliked the blue staining of their urine, 5 patients remained on the active treatment after completion of the trial.

Bipolar Disorder a Treatable Illness

"The first take-home message is that methylene blue is a good treatment for patients with bipolar disorder who have not stabilized on their current treatment," Dr. Alda said.

"The second message is that people with bipolar disorder can actually do quite well with treatment and can often improve to the point of full functioning. When we see patients who are quite a bit better, we should not be fully satisfied, and instead should aim for as complete a recovery as we can."

"The treatment is ideal for patients who do not improve 100% — who are instead maybe at 70% to 80%, so they have stopped having depression and manic episodes but they are not quite there," he added. "These patients would be candidates for methylene blue. It's a 'fine-tuning' rather than a primary mood stabilizing treatment."

An "Interesting Study"

Dr. David Nutt

"This is a very interesting study. It takes me back to when I started psychiatry about 30 years ago. There was a team from Dundee [Scotland] reporting that methylene blue might be useful in manic depressive psychosis," David Nutt, DM, who is Edmund J. Safra professor of neuropsychopharmacology at University College in London, United Kingdom, told Medscape Medical News. "There's a cyclical resurrection of methylene blue in psychiatry because it seems to be biologically active, but the problem is that there's a history of these trials not being replicated."

"Residual symptoms are common in patients with bipolar disorder, as they are in every psychiatric disorder, and no one gets fully better except perhaps patients with panic disorder," Dr. Nutt explained. "Residual symptoms are disabling and they make patients vulnerable to relapse, so it's important to aim to get people from a state of recovery to a state of remission. I welcome studies in this area. If methylene blue works in this setting, that will be great, but the data from the present study need to be replicated. Time will tell."

The study was funded by Stanley Medical Research Institute in Washington DC. Dr. Alda and Dr. Nutt have disclosed no relevant financial relationships.

24th Congress of the European College of Neuropsychopharmacology (ECNP). Abstract P.2.e.001. Presented September 5, 2011.

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