A study led by Massachusetts General Hospital (MGH) investigators identifies two subanesthetic dosage levels of the anesthetic drug ketamine that appear to provide significant symptom relief to patients with treatment-resistant depression. In the October 2018 issue of Molecular Psychiatry they describe finding that single intravenous doses of 0.5 mg/kg and 1.0 mg/kg were more effective than an active placebo in reducing depression symptoms over a three-day period. Two lower dosage levels that were tested did not provide significant symptom relief, although some improvement was noted with the lowest 0.1 mg/kg dose.



“Treatment resistance in depression is a major issue, with more than half of patients not responding adequately to standard, appropriate antidepressant treatment,” says Maurizio Fava, MD, executive director of the Clinical Trials Network & Institute in the MGH Department of Psychiatry and senior author of the Molecular Psychiatry paper. “There are only a few approved therapies that can help some patients with treatment-resistant depression, so we critically need more options to choose from.”



Long used as a general anesthetic drug, ketamine has been found in several studies to rapidly relieve depression symptoms when given at low, subanesthetic doses. Most of those studies used a standard 0.5 mg/kg intravenous dose, leaving determination of the optimal dosage unclear. To investigate that question, the study tested four different ketamine dosages – 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg and 1.0 mg/kg – compared with an “active” placebo, a drug that induces side effects, the lack of which could lead participants to realize they are not receiving the medication being tested, potentially biasing their perception of symptom improvement.



The study enrolled 99 adults with treatment-resistant depression at six research centers – MGH, Baylor College of Medicine/Debakey VA Medical Center, Icahn School of Medicine at Mt. Sinai, Stanford University School of Medicine, University of Texas/Southwestern Medical Center, and Yale University. Participants were randomized into five groups – the four dosage levels and the active control group, with neither they nor the research staff aware of group assignments – and continued taking their previously prescribed antidepressants during the study period.



Participants were assessed with a standard depression rating scale the day they received the infusion and 2, 3, 5, 7, 14 and 30 days later. Additional instruments measured aspects of mood and suicidal thought. Dissociative symptoms such as memory loss and feelings of detachment from reality were assessed during and after ketamine infusion, and vital signs were measured after treatment and at all follow-up visits.



On the standard depression scale, participants receiving ketamine had significantly greater symptom improvement during the three days after infusion than did those in the active control group. Comparison of dosage levels, after adjusting for multiple comparisons, found statistically significant improvement compared to the control group only for participants receiving 0.5 mg/kg and 1.0 mg/kg doses. The low 0.1 mg/kg dose produced significant relief only prior to adjustment, and the 0.2 mg/kg dose did not show any significant benefits. It is possible that the lack of efficacy at the 0.2 mg/kg level could reflect the small size of treatment groups and the fact that participants in that group tended to be more treatment resistant to begin with, the authors note.



For most participants in the higher-dose groups, the benefits of ketamine treatment began to decrease on the third day after treatment and were no longer detectable after five days. There were no significant differences in the occurrence of adverse events among all study participants.



Co-author Cristina Cusin, MD, who directs the MGH Psychiatry ketamine clinic, says, “These results support the clinical observation that one size – in this case the most studied dose of 0.5 mg/kg – does not fit all, as some patients may require a lower-than-average dose; and each patient needs a tailored treatment plan that may include ketamine, together with other medications and talk therapy. We still do not understand which factors play a role in determining lack of response to treatments or which is the best possible strategy for patients suffering from severe depression.”



Fava, the Slater Family Professor of Psychiatry at Harvard Medical School, adds, “Along with supporting the efficacy of intravenous ketamine for patients with treatment-resistant depression, our study also suggests that even lower doses may be effective in some patients. Further investigation should examine the efficacy of repeat doses of ketamine, as well as whether higher doses may require less frequent administration.”



Additional co-authors of the Molecular Psychiatry paper are Marlene Freeman, MD, Martina Flynn, Bettina Hoeppner, PhD, Dawn Ionescu, MD, and George Papakostas, MD, MGH Psychiatry; Lee Chang, MD, and Sanjay Matthew, MD, Baylor/Debakey VA Medical Center; Dan Iosifescu, MD, MSc, and James Murrough, MD, Icahn/Mt. Sinai; Charles Debattista, MD, DMH, and Alan Schatzberg, MD, Stanford; Madhukar Trivedi, MD, and Manish Jha, MD, UTexas/Southwestern; and Gerard Sanacora, MD, PhD, and Samuel Wilkinson, MD, Yale. The study was supported by National Institute for Mental Health contract HHSN271201100006I.



Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."



