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Letters to the Editor   |    
Long-Term Maintenance With Intramuscular Ketamine for Treatment-Resistant Bipolar II Depression
Cristina Cusin, M.D.; George Q. Hilton, M.D.; Andrew A. Nierenberg, M.D.; Maurizio Fava, M.D.
Am J Psychiatry 2012;169:868-869. doi:10.1176/appi.ajp.2012.12020219
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Boston
Dover, N.H.
Boston

Dr. Cusin and Dr. Hilton report no financial relationships with commercial interests.

Dr. Nierenberg has served as a consultant to APA, Appliance Computing (Mindsite), AstraZeneca, Basliea, Brain Cells, Brandeis University, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor, Eli Lilly, EpiQ, Johnson & Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Schering-Plough, Shire, Takeda/Lundbeck Pharmaceuticals, and Targacept; he has received grant/research support through Massachusetts General Hospital (MGH) from NIMH, PamLabs, Pfizer Pharmaceuticals, and Shire; he has received honoraria from Belvoir Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, IMEDEX, MJ Consulting, New York State, Medscape, MBL Publishing, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin, University of Pisa, APSARD, ISBD, and SciMed; he is a presenter for the MGH Psychiatry Academy, whose programs were supported through Independent Medical Education (IME) grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen Pharmaceuticals; he serves on advisory boards for Appliance Computing, Brain Cells, Eli Lilly, Johnson & Johnson, and Takeda/Lundbeck, and Targacept; he owns stock options in Appliance Computing and Brain Cells; he is named for copyrights through MGH to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-Åsberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute.

Dr. Fava receives research support or advisory, consulting, speaking, or publishing fees from Abbott Laboratories, Adamed, Advanced Meeting Partners, Affectis Pharmaceuticals AG, Alkermes, APA, Amarin Pharma, American Society of Clinical Psychopharmacology, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Belvoir Media Group, Best Practice Project Management, BioMarin Pharmaceuticals, BioResearch, Biovail Corporation, Boehringer Ingelheim GmbH, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, Clintara, CME Institute/Physicians Postgraduate Press, CNS Response, Compellis Pharmaceuticals, Covance, Covidien, Cypress Pharmaceutical, DiagnoSearch Life Sciences (P) Ltd., Dainippon Sumitomo Pharma Co., Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, ElMindA, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Ganeden Biotech, GenOmind, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenix, Icon Clinical Research, Imedex, Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, Knoll Pharmaceuticals Corp., Labopharm, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, MSI Methylation Sciences, NARSAD, National Center for Complementary and Alternative Medicine, National Institute of Drug Abuse, Naurex, NeuralStem, Neuronetics, NextWave Pharmaceuticals, NIMH, Novartis AG, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Photothera, Precision Human Biolaboratory, Prexa Pharmaceuticals, PsychoGenics, Psylin Neurosciences, Puretech Ventures, RCT Logic, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis US LLC, Schering-Plough Corporation, Sepracor, Servier Laboratories, Shire, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Takeda Pharmaceutical Company Limited, Tal Medical, Tetragenex Pharmaceuticals, TransForm Pharmaceuticals, Transcept Pharmaceuticals, United BioSource, Vanda Pharmaceuticals, and Wyeth-Ayerst Laboratories; he has equity or holdings in Compellis and receives other income from a patent for Sequential Parallel Comparison Design and patent application for a combination of azapirones and bupropion in major depressive disorder; he receives copyright royalties for the MGH Cognitive & Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs & Symptoms, and SAFER; and he has a patent for research and licensing of SPCD with RCT Logic, Lippincott, Wolkers Kluwer, and World Scientific Publishing.

Accepted for publication in May 2012.

Copyright © American Psychiatric Association

Accepted May , 2012.

To the Editor: Ketamine, an N-methyl-d-aspartic acid (NMDA) receptor antagonist, is being actively explored as a rapid treatment for resistant depression (1, 2), but its long-term efficacy has not been investigated. We report on two patients with bipolar II disorder who responded to intramuscular ketamine augmentation. Both patients provided consent for publication.

A 57-year-old woman with bipolar II disorder and attention deficit hyperactivity disorder (ADHD) had depressive episodes that did not respond to multiple adequate medication trials, including ECT. During the last depressive episode, she had 12 adequate antidepressant trials that failed to relieve her symptoms. Her current medications were venlafaxine (150 mg/day), lamotrigine (100 mg/day), and methylphenidate (40 mg b.i.d.). Her depressive symptoms (low mood, fatigue, anhedonia, and passive suicidal ideation) began to improve after the third infusion of ketamine (administered twice a week, 0.5 mg/kg over 40 minutes; weight=122 lbs, height=5'2"); however, her depression returned 10 days after the fifth and final infusion. Trials of oral ketamine (210 mg/day by capsule, three times per week) and intranasal ketamine (200 mg/mL, three sprays, three times per week) for 3 weeks each did not provide relief. Next, the patient tried 32 mg and then 50 mg of intramuscular ketamine, and she experienced complete remission of her depression within a few days. The schedule was empirically determined, and 50 mg i.m. every 4 days was continued for 5 months until she had partial relapse. The dosage was increased to 70 mg every 4 days, and she remained completely asymptomatic for 4 months. She experiences side effects of irritability, nightmares, and dissociative feelings.

A 48-year-old woman with a history of bipolar II disorder, ADHD, fibromyalgia, hypothyroidism, chronic depression, and persistent suicidal ideation for the preceding 5 years obtained no relief from aggressive pharmacological treatment with mood stabilizers, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. She tried ketamine at 150 mg p.o. three times per week for 2 weeks with no benefit (weight=225 lbs., height=5'5"). While taking lamotrigine (150 mg/day), levothyroxine (75 μg/day), pregabalin (200 mg/day), armodafinil (250 mg/day), and oxcarbazepine (900 mg/day), she received 100 mg of intramuscular ketamine but did not tolerate the dissociative symptoms; the dosage was reduced to 50 mg, and treatment was repeated every 3 days with improvement after 1 week. She had a partial relapse after 6 months, and bupropion was added. While she has not reached remission, she is no longer suicidal and has continued to work for the past 6 months. Side effects included headaches and irritability.

These preliminary case reports indicate that intramuscular ketamine is a potential treatment for treatment-resistant bipolar depression. Oral ketamine has poor bioavailability (17%–20% compared with 93% intramuscular), and in these cases it did not produce any antidepressant effect. In contrast, intramuscular ketamine remained efficacious after months and was well tolerated, with adverse effects of moderate anxiety, irritability, dissociative feelings, and headaches. Intramuscular ketamine for treatment-resistant bipolar depression is worthy of further study to assess its long-term efficacy, adverse effects (cystitis, hepatotoxicity, or potential neurological effects), and possible risks of abuse and dependence.

Zarate  CA  Jr;  Singh  JB;  Carlson  PJ;  Brutsche  NE;  Ameli  R;  Luckenbaugh  DA;  Charney  DS;  Manji  HK:  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.  Arch Gen Psychiatry 2006; 63:856–864
[CrossRef] | [PubMed]
 
Zarate  CA  Jr;  Brutsche  NE;  Ibrahim  L;  Franco-Chaves  J;  Diazgranados  N;  Cravchik  A;  Selter  J;  Marquardt  CA;  Liberty  V;  Luckenbaugh  DA:  Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.  Biol Psychiatry 2012; 71:939–946
[CrossRef] | [PubMed]
 
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References

Zarate  CA  Jr;  Singh  JB;  Carlson  PJ;  Brutsche  NE;  Ameli  R;  Luckenbaugh  DA;  Charney  DS;  Manji  HK:  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.  Arch Gen Psychiatry 2006; 63:856–864
[CrossRef] | [PubMed]
 
Zarate  CA  Jr;  Brutsche  NE;  Ibrahim  L;  Franco-Chaves  J;  Diazgranados  N;  Cravchik  A;  Selter  J;  Marquardt  CA;  Liberty  V;  Luckenbaugh  DA:  Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.  Biol Psychiatry 2012; 71:939–946
[CrossRef] | [PubMed]
 
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