— John Gever, MedPage Today, August 2, 2010. Ketamine Cuts Depression in Bipolar Illness. Originally appeared at: http://www.medpagetoday.com/Psychiatry/Depression/21499 The anesthetic ketamine (sometimes illicitly used as a recreational drug) produced rapid alleviation of severe depression in patients with treatment-resistant bipolar illness in a small clinic trial. In an 18-patient randomized trial, a single infusion of intravenous ketamine knocked 10 points off Montgomery-Asberg Depression Rating Scale (MADRS) scores in 40 minutes compared with a placebo treatment, reported Carlos Zarate Jr., MD, of the National Institute of Mental Health in Bethesda, Md., and colleagues. The difference between ketamine and placebo groups in mean MADRS scores grew to more than 13 points on the second day after the ketamine infusion, the researchers wrote in the August issue of Archives of General Psychiatry. “To our knowledge, this is the first article detailing the rapid antidepressant effects of a single infusion of an NMDA [N-methyl-D-aspartate] antagonist in patients with treatment-resistant bipolar depression,” Zarate and colleagues wrote. Zarate had led an earlier randomized trial of ketamine in patients with severe unipolar depression that also found rapid and pronounced benefits. Numerous other researchers have reported similar findings in case reports and in small, uncontrolled series. Conventional antidepressants all require several weeks of treatment before effects are apparent. Adherence can suffer in the meantime, as patients lose interest in taking a drug that doesn’t seem to be working. Nevertheless, even though ketamine is an approved prescription drug, it does not appear to have caught on clinically — perhaps because its label includes a boxed warning for “vivid imagery, hallucinations, or emergence delirium” when used as an anesthetic. This effect has led to the illicit use of ketamine as a “rave” party drug, dubbed “Special K.” Quasi-psychedelic reactions were not uncommon in the new study. Zarate and colleagues indicated that at least 10% of participants reported “feeling woozy or loopy” or having “odd sensations,” as well as more mundane effects such as drowsiness, cognitive impairment, nausea, blurred vision, and headache. On the other hand, given the severe and disabling depression seen in study participants, such effects — which Zarate and colleagues described as nonserious — may be a small price to pay. The researchers noted that their patients had failed to respond to a mean of seven previous antidepressant drugs, and 55% had not responded to electroconvulsive therapy. “The toll of this protracted and refractory illness on the subjects was evident, in that two- thirds of participants were on psychiatric disability and nearly all were unemployed,” Zarate and colleagues noted. Patients in the study remained on bipolar illness medications including lithium or valproate. They were hospitalized for an average of nine weeks prior to starting the randomized treatment, during which their responses to these mood stabilizers were assessed and stability of depression symptoms could be monitored in a relatively controlled setting. MADRS scores averaged about 31 in the treatment group and 33 in the control group at the start of the randomized treatment phase. Just 40 minutes after a ketamine infusion of 0.5 mg/kg — the standard anesthetic dose is 1 to 4.5 mg/kg — mean MADRS scores in the active treatment group dropped to 18, whereas scores in the placebo group declined to 28. Scores in the ketamine group remained stable through the second day after infusion, then returned to near baseline levels (not significantly different from the placebo group) by day seven. Very similar patterns were seen in scores on the standard Hamilton and Beck depression evaluations. Zarate and colleagues noted that the onset of significant relief was even faster in this sample than in the earlier trial with unipolar depressed patients — in which relief took 110 minutes. They suggested that this discrepancy may reflect concomitant treatment with lithium or valproate, and the more severe depression in the current study’s sample. The researchers cited several limitations to their study. One of the most important may be the hallucinogenic side effects of ketamine, which might have clued patients to whether they had received the active drug as opposed to placebo. Zarate and colleagues noted that a significant number of placebo patients experienced similar adverse effects, and there was no apparent relationship between adverse effects and treatment efficacy in the ketamine group. Nevertheless, the researchers conceded that blinding could have been compromised, “potentially confounding the results.” “Future studies using ketamine will have to address the limitation of blinding and may include an active comparator with central nervous system effects,” they suggested. Zarate and colleagues also noted that the trial was small and that their patients were very severely depressed — with a mean duration of illness of nearly 30 years — which is not representative of most patients with bipolar depression. In addition, they emphasized that it is still unknown whether the improvements in symptoms of severe depression seen with ketamine can be maintained — or if so, how. Zarate is currently leading what would be the first large trial of ketamine for treating depression. The 164-patient study in unipolar depression, which began recruitment in 2004, is expected to be completed in 2014, according to its listing on Clinicaltrials.gov. This article discusses the results of a new small study funded by the NIH examining the effectiveness of ketamine in helping people suffering with treatment-resistant bipolar disorder.