Several available agents in addition to methylene blue are being investigated for bipolar disorder and were included in a review by Marsal Sanches and Jair Soares1 of the University of Texas, in Current Psychiatry Reports. Those with favorable, albeit preliminary, results are recapped:
Compounds for Mania, Mixed State
•memantine (Namenda) for Alzheimer’s. Possible mechanism: N-methyl-D-asparatate (NMDA) glutamate receptor antagonist. Clinical evaluation: Demonstrated potential to relieve “manic-like” symptoms in animal models; appeared beneficial in two open-label studies as augmentation.
•tamoxifen (Cytogen) estrogen antagonist. Possible mechanism: inhibitory effect on protein kinase C, involved in the intracellular calcium influx which is purported to be hyperactive in bipolar disorder. Clinical Evaluation: Three controlled trials have associated tamoxifen as monotherapy or as augmentation with improved scores on the Young Mania Rating Scale (YMRS). The potential for long-term use is confounded by side effects associated with estrogen receptor blockade, as well as the risk of rebound manic symptoms upon discontinuation. The Canada Network for Mood and Anxiety Treatment (CANMAT) lists it as a third-line option.
•allopurinol (Zyloprim) for gout. Possible mechanism: A xanthine oxidase inhibitor which effects the purinergic system, hypothesized to be involved in the pathophysiology of mania. Clinical Evaluation: Short-term trials suggest benefit as an adjunct to mood stabilizer or antipsychotic; with two additional short-term studies, and one long-term assessment of its use for maintenance currently underway.
Possibilities for Bipolar Depression
•ketamine (Ketalar), anesthetic. Possible mechanism: NMDA receptor antagonist. Clinical Evaluation: IV infusion as augmentation in double-blind, controlled trial in patients receiving lithium or valproate. Two doses, separated by two weeks, were associated with rapid, but transient symptom improvement (40 minutes to 3 days).
•riluzole (Rilutek) for amyotrophic lateral sclerosis. Possible mechanism: NMDA receptor antagonist. Clinical Evaluation: Open label study suggests symptom improvement, and correlated this with increases in n-acetyl aspartate brain levels, which the reviewers describe as a marker of neuronal viability. A controlled trial is underway. CANMAT lists it as a 3rd line option for bipolar depression.
•n-acetylcysteine (Mucomyst), mucolytic/antidote for acetaminophen poisoning. Possible mechanism: glutathione substitute effects hepatic oxidative metabolism. Clinical Evaluation: Study of adjunctive treatment in bipolar disorder suggested benefit during treatment, supported by the observation of the effect dissipating with discontinuation. Similar results were apparent from analysis of sub-population with bipolar II disorder.
•agomelatine (Veldoxan) melatonin receptor agonist. Possible mechanism: restore circadian rhythms disrupted in mood disorder. Clinical evaluation: Several trials for major depression, but only one, open-label study in bipolar depression. It use as an adjunct to mood stabilizer appeared beneficial.
•pramipexole (Mirapex) antiparkinson. Possible mechanism: dopamine agonist. Clinical evaluation: Two controlled studies associated pramipexole as adjunct to a mood stabilizer with improved depressive symptoms in, respectively, bipolar depression and bipolar type II. In addition, the reviewers note a subsequent positron emission tomography (PET) study revealed marked reductions in regional metabolism in the orbitofrontal cortex in which, they indicate, elevated metabolic activity has been documented to occur during depressive mood states.
•modafinil (Provigil) for narcolepsy. Possible mechanism: stimulant, effecting multiple neurotransmitter systems. Clinical evaluation: A controlled study of modafinil as an adjunct suggested benefit, but the reviewers cite case reports of the stimulant prompting affective switching to mania.
[Editor's Note: For information on methylene blue for bipolar disorder, click here.]
1. Sanches M, Soares JC. New drugs for bipolar disorder. Curr Psychiatry Rep. Published on-line ahead of print, August 30, 2011. DOI 10.1007/s11920-011-0231-1. Accessed September 28, 2011.