Ketamine Yields Swift Antidepressant Effect in Treatment of Refractory Bipolar Depression

By: Megan Brooks

MedscapeToday

—-

Ketamine Yields Swift Antidepressant Effect in Treatment of Refractory Bipolar

Depression.

Megan Brooks, MedscapeToday, August 3, 2010.

Originally appeared at:

http://www.medscape.com/viewarticle/726219

August 3, 2010 — A single intravenous dose of the N-methyl-D-aspartate (NMDA)

antagonist ketamine hydrochloride produces a robust antidepressant effect within 40

minutes in patients with treatment-resistant bipolar depression (BPD), according to

results of a controlled “proof-of-concept” study published in the August issue of the

Archives of General Psychiatry.

“What is particularly noteworthy,” Carlos A. Zarate, Jr., MD, told Medscape Medical

News, “is that we demonstrated that it is possible to produce an onset of antidepressant

effects in treatment-resistant BPD within 1 hour, which usually takes weeks or longer.”

“In my opinion, these results and other related work raise the bar in drug development

for BPD in that we should develop treatments that result in an antidepressant response in

hours instead of weeks,” added Dr. Zarate, who is chief of the Experimental Therapeutics

& Pathophysiology Branch, Division of Intramural Research Program, National Institute

of Mental Health, Bethesda, Maryland.

Several lines of evidence have recently converged to suggest that dysfunction in the

glutamatergic system, particularly the NMDA receptor complex, plays a key role in the

pathophysiology of BPD. The new study supports this line of thinking.

The randomized, placebo-controlled, double-blind, crossover, add-on study involved 18

adults with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) BPD

resistant to lithium or valproate. The subjects had a mean age of 47.9 years and a mean

length of illness of 27.6 years.

They were maintained at therapeutic levels of lithium or valproate and given either an

infusion of ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart.

Thirteen of the 18 subjects (72%) completed both study phases.

The Montgomery-Asberg Depression Rating Scale (MADRS) was used to rate subjects

at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 after

infusion. Change in MADRS score was the primary outcome.

Robust, Rapid Effect

According to the investigators, within 40 minutes, depressive symptoms improved

significantly in those receiving ketamine compared with those receiving placebo (d =

0.52; 95% confidence interval [CI], 0.28 – 0.76); this improvement was greatest at day 2

(d = 0.80; 95% CI, 0.55 – 1.04) and remained significant through day 3.

Twelve of 17 subjects (71%) responded to ketamine and 1 of 16 (6%) responded to

placebo at some point during the study, the researchers say, with response defined as

50% improvement from baseline on the MADRS. The median time to response was 40

minutes. Response to ketamine lasted for an average of 6.8 days (SE, 1.4 days); 4 patients

responded for 1 week, and 3 additional patients had a response lasting 2 weeks or more.

In addition to the MADRS, statistically significant differences favoring ketamine were

also evident on the Hamilton Scale for Depression, the self-rated Beck Depression

Inventory, the visual analog scale for depression and anxiety, and the Hamilton Anxiety

Rating Scale.

“These findings are particularly noteworthy because a substantial proportion of study

participants had been prescribed complex polypharmacy regimens in the past with

substantial treatment failures,” Dr. Zarate and colleagues note in their report. The average

number of past antidepressant trials was 7, and more than 55% of participants failed to

respond to electroconvulsive therapy.

The drug was generally well tolerated; dissociative symptoms, only at the 40-minute

time point, was the most common adverse effect, a finding “consistent with all published

studies using ketamine,” the study authors note. Manic symptoms developed in 1 subject

receiving ketamine and 1 receiving placebo.

Landmark Contributions

Joseph R. Calabrese, MD, director of the Mood Disorders Program and codirector of

the Bipolar Disorders Research Center, University Hospitals Case Medical Center,

Case Western Reserve University, Cleveland, Ohio, told Medscape Medical News that

Dr. Zarate “continues to make landmark contributions to the field of mood disorders in

general and bipolar disorder in particular.

“His work has shown that increased glutamatergic release results in an almost immediate

acute antidepressant response in patients who are in the depressed phase of bipolar I

and II disorder. It is the depressed phase of bipolar disorder where our patient live their

symptomatic lives, suffer the most, and, in all too many instances, end their life by

completing a suicide attempt,” added Dr. Calabrese, who was not involved in the current

study.

Dr. Zarate and colleagues note that the small size of the study and the inclusion only of

the subgroup of patients with treatment-resistant BPD who were relatively late in their

illness are 2 limitations of their study. The findings can therefore not be generalized to

other patients with BPD with different illness and course characteristics (ie, rapid cycling

course and current substance use disorders).

They also say it is possible, although unlikely, that the response seen was due to lithium

or valproate rather than ketamine. It is also possible, although again unlikely, they say,

that the patients who got better with ketamine had cycled out of their major depressive

episode.

The transitory dissociative symptoms seen with ketamine could have compromised the

study blinding.

“The primary shortcoming of this research that limits its clinical utility is the method by

which ketamine needs to be administered, by intravenous infusions,” said Dr. Calabrese.

He is hopeful the pharmaceutical industry will “use Dr. Zarate’s scientific thesis and now

supportive data to develop new treatments that have not only robust short- and long-

term efficacy in the depressed phase of bipolar I or II disorder, but now, with almost

immediate onset.”

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