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Intravenous Ketamine May Rapidly Reduce Suicidal Thinking in Depressed Patients: Small Study

Repeat ketamine infusions decreased, and for some, eliminated, suicidal thoughts in outpatients with treatment-resistant depression.

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking – including lithium and clozapine – can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period – about five times less than a typical anesthetic dose – and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits – one dropped out because of ketamine side effects and one had a scheduling conflict – most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

Chemical structure of ketamine.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period – about five times less than a typical anesthetic dose – and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week. Image is for illustrative purposes only. Credit: Mrgreen71.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

About this psychopharamcology research

Additional co-authors of the Journal of Clinical Psychiatry paper are Michaela Swee, Kara Pavone, Lee Baer, PhD, Maren Nyer, PhD, Paolo Cassano, MD, David Mischoulon, MD, PhD, Jonathan Alpert, MD, PhD, Maurizio Fava, MD, and Cristina Cusin, MD, Depression and Clinical Research Program, MGH Psychiatry; Norman Taylor, MD, Oluwaseun Akeju, MD, and Emery Brown, MD, PhD, MGH Department of Anesthesia, Critical Care and Pain Medicine; and Matthew K. Nock, PhD, Harvard University Department of Psychology.

Funding: Support for the study includes National Center for Advancing Translational Science grant 8UL1 TR000170-05 to the Harvard Clinical and Translational Science Center.

Source: Massachusetts General Hospital
Image Credit: The image is credited Mrgreen71 and is licensed CC BY-SA 3.0
Original Research: Abstract for “Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study” by Dawn F. Ionescu, Michaela B. Swee, Kara J. Pavone, Norman Taylor, Oluwaseun Akeju, Lee Baer, Maren Nyer, Paolo Cassano, David Mischoulon, Jonathan E. Alpert, Emery N. Brown, Matthew K. Nock, Maurizio Fava, and Cristina Cusin in Journal of Clinical Psychiatry. Published online May 2016 doi:10.4088/JCP.15m10056


Abstract

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study

Background: Ketamine rapidly reduces thoughts of suicide in patients with treatment-resistant depression who are at low risk for suicide. However, the extent to which ketamine reduces thoughts of suicide in depressed patients with current suicidal ideation remains unknown.

Methods: Between April 2012 and October 2013, 14 outpatients with DSM-IV–diagnosed major depressive disorder were recruited for the presence of current, stable (≥ 3 months) suicidal thoughts. They received open-label ketamine infusions over 3 weeks (0.5 mg/kg over 45 minutes for the first 3 infusions; 0.75 mg/kg over 45 minutes for the last 3). In this secondary analysis, the primary outcome measures of suicidal ideation (Columbia-Suicide Severity Rating Scale [C-SSRS] and the Suicide Item of the 28-item Hamilton Depression Rating Scale [HDRS28-SI]) were assessed at 240 minutes postinfusion and for 3 months thereafter in a naturalistic follow-up.

Results: Over the course of the infusions (acute treatment phase), 7 of 14 patients (50%) showed remission of suicidal ideation on the C-SSRS Ideation scale (even among patients whose depression did not remit). There was a significant linear decrease in this score over time (P < .001), which approached significance even after controlling for severity of 6-item Hamilton Depression Rating Scale (HDRS6) core depression items (P = .05). Similarly, there were significant decreases in the C-SSRS Intensity (P < .01) and HDRS28-SI (P < .001) scores during the acute treatment phase. Two of the 7 patients who achieved remission during the acute treatment phase (29%) maintained their remission throughout a 3-month naturalistic follow-up.

Conclusions: In this preliminary study, repeated doses of open-label ketamine rapidly and robustly decreased suicidal ideation in pharmacologically treated outpatients with treatment-resistant depression with stable suicidal thoughts; this decrease was maintained for at least 3 months following the final ketamine infusion in 2 patients.

Trial Registration: ClinicalTrials.gov identifier: NCT01582945

“Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study” by Dawn F. Ionescu, Michaela B. Swee, Kara J. Pavone, Norman Taylor, Oluwaseun Akeju, Lee Baer, Maren Nyer, Paolo Cassano, David Mischoulon, Jonathan E. Alpert, Emery N. Brown, Matthew K. Nock, Maurizio Fava, and Cristina Cusin in Journal of Clinical Psychiatry. Published online May 2016 doi:10.4088/JCP.15m10056

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