Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.
Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.



We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.



Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.



The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.



Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada malda@dal.ca.
Martin
M
Alda
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Margaret
M
McKinnon
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Ryan
R
Blagdon
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Julie
J
Garnham
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Susan
S
MacLellan
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Claire
C
O'Donovan
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Tomas
T
Hajek
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Cynthia
C
Nair
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Serdar
S
Dursun
Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Margaret McKinnon, PhD, Department of Psychiatry and Neuroscience, McMaster University, Hamilton, Mood Disorders Program, St Joseph's Healthcare, Hamilton and Homewood Research Institute, Guelph, Ontario; Ryan Blagdon, MSc, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Julie Garnham, RN, BN, Susan MacLellan, RN, Capital District Health Authority, Halifax, Nova Scotia; Claire O'Donovan, MB, FRCPC, Tomas Hajek, MD, PhD, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Cynthia Nair, MD, FRCPC, Associate Medical Clinic, Prince Albert, Saskatchewan; Serdar Dursun, MD, PhD, FRCPC, Department of Psychiatry, University of Alberta, Edmonton, Alberta; Glenda MacQueen, MD, PhD, FRCPC, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Glenda
G
MacQueen
D000328:Adult; D001007:Anxiety / Q000188:drug therapy* / Q000209:etiology; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy*; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology; D018592:Cross-Over Studies; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008751:Methylene Blue / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D055815:Young Adult
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D014227:Triazines; D008751:Methylene Blue; D000077213:Lamotrigine