Ketamine: Key Predictor of Treatment Response for MDD Identified

Nancy A. Melville

April 12, 2018

WASHINGTON — More intense dissociative symptoms exhibited during ketamine infusion for severe depression, particularly depersonalization, may be key predictors of treatment response. In addition, new safety and efficacy data for off-label use of the drug are encouraging.

Mark Niciu, MD, PhD, of the National Institute of Mental Health (NIMH), and colleagues analyzed three studies involving 126 patients with treatment-resistant depression. They found a significant association between dissociative symptoms experienced during infusion and reductions in depressive symptoms, as reflected in some, but not all, dissociation subscale measures.

"The findings suggest that mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded," Niciu told delegates attending the Anxiety and Depression Association of America (ADAA) Conference 2018.

The results were also published in the May issue of the Journal of Affective Disorders.

In another presentation at the ADAA conference, Samuel Wilkinson, MD, assistant director of the Depression Research Program at Yale University, New Haven, Connecticut, reported details from his institution's experience with the use of ketamine during a period of more than 30 months in patients with severe and treatment-resistant mood disorders.

Among 50 patients who received one to four treatments, the response rate, defined as a 50% improvement in symptoms, was approximately 50%; the remission rate was 27.3%.

In a subset of 14 patients who received 12 to 45 total treatments during a period of 14 to 126 weeks, there was no evidence of cognitive decline or delusions, as measured with the CogState cognitive assessment tool, Wilkinson reported.

Soaring Interest

Because conventional antidepressants can take weeks if not months to reach full effect and are completely ineffective in many patients, interest in ketamine, an N-methyl-d-aspartate receptor antagonist, as a rapid-acting treatment for severe mood disorders has soared in recent years, noted Niciu.

Previous studies have reported significant improvements in depression following a single ketamine infusion, with improvements lasting from several days to a week. However, not everyone responds to ketamine.

In the new study, 84 of the 126 participants had major depressive disorder, and 42 had bipolar depression. All were treated with the standard ketamine treatment for depression, consisting of a single subanesthetic dose (0.5 mg/kg) delivered by infusion over 40 minutes.

Patients were followed for at least 1 week post infusion and, in one of the three studies that were assessed, for up to 28 days.

In one of the studies, dissociative effects, measured using the Clinician-Administered Dissociative States Scale (CADSS) at baseline and at the end of infusion, were associated with symptoms of depression, as measured with the Hamilton Depression Rating Scale (HDRS-17), at day 7 following the infusion (P = .04).

Scores on the depersonalization subscale of the CADSS were related to percentage change in HDRS-17 score in all three studies and at all time points (P = .04).

Scores on the subscale of derealization were associated with percentage change in HDRS score on day 7 post infusion in one study (P = .01).

No association was observed between amnesia symptoms during infusion and reduction in depression, as reflected in percentage change in HDRS score.

Mechanistic Similarities

"What really jumped out at us was the depersonalization subscale," Niciu said.

He speculated that depersonalization in particular may relate to some of the deeper aspects of depression, more so than derealization, which involves detachment from reality, or amnesia.

"There might be mechanistic similarities between depersonalization and an antidepressant response," Niciu explained.

"These are people with a highly introspective disorder and are often focused on their inner self. If you can detach them from that for a period of time and disconnect them from the subjective sensations, then that may result in a better antidepressant response, but that's a hypothesis," he said.

The findings suggest that the use of the depersonalization scale could represent a relatively easy way to assess the possibility of the patient's responding to ketamine.

"In the clinical setting, if someone is administering ketamine and doesn't have much time and just wants to get a sense of how a patient might respond, the CADSS depersonalization subscale is something they might want to administer," Niciu said.

"It is easy to administer — it's only five items, and those who tend to score higher on that subscale may be more likely to be responders," he added.

Relevance Questioned

The study was an extension of earlier research from the investigators linking the degree of dissociative symptoms with ketamine's antidepressant effects.

On the basis of those findings, some clinicians already try to achieve the effects in order to evoke a better response, said Sanjay Mathew, MD, professor of psychiatry and behavioral sciences, Baylor College of Medicine and the Michael E. Debakey VA Medical Center, Houston, Texas, while commenting on the study at the meeting.

"Often, anesthesiologists and psychiatrists at ketamine clinics will start at 0.5 mg/kg and titrate the dose to mild dissociation," said Matthew. "They often want the patient to feel buzzed, because that's when they feel confident that they've hit the 'sweet spot' of NMDA modulation."

He noted that another NIMH study of 99 patients, which is currently under review, showed that the best outcomes, as reflected in scores on depression scales, were achieved with the standard 0.5 mg/kg dose in comparison with the 1.0 mg/kg dose and the very low dose of 0.1 mg/kg, which were associated with a high degree of dissociation.

"Clearly, the message from that study is that you don't need to dissociate to get better," he said.

Nevertheless, "the issue is fascinating, with high clinical relevance in terms of how clinicians are using ketamine in the community," Mathew said.

However, Wilkinson noted that he has not seen similar patterns in his patients who were treated with ketamine, and he questioned the use of the CADSS tool for determining dissociation symptoms in the study.

"We have not observed that the level of dissociation and depersonalization predict response," he told Medscape Medical News.

"I am skeptical of this finding, as the CADSS instrument was not designed for use in ketamine studies and in my opinion does not do a great job at capturing this phenomenon related to ketamine," he added.

Wilkinson noted that the dissociative symptoms that can occur with ketamine treatment do not appear to subside after multiple infusion sessions.

"In my experience treating patients, there seem to be a group of patients who always develop fairly significant symptoms, even though they have been treated 20 times or more with ketamine," he said.

Longer-term Outcomes

During the presentation of his own study, Wilkinson reported that 21 participants (38%) were men and 96% were being treated with concomitant medications during the acute course. These medications included antidepressants (72.2%), antipsychotics (53.7%), mood stabilizers (37%), lithium (18.5%), and sedatives/hypnotics (50%).

Patients were initially treated intravenously with a single or double infusion of 0.5 mg/kg over 40 minutes. However, patients were later transitioned to a four-dose protocol administered twice per week over 2 weeks.

The response rate was about 50%, and the remission rate was 27.3% among 50 patients who received one to four treatments.

Although there was no evidence of cognitive decline or delusions, one person discontinued infusion because of intolerability, one discontinued because of hypertension, one experienced relapse of cannabis use disorder, and three required rehospitalization for suicidal ideation or suicide attempts.

There were two completed suicides, one occurring 10 months after last contact with the program, and one 4 months after last contact.

Wilkinson noted that the 50% response rate is somewhat lower than rates reported in clinical trials, which may reflect a real-world setting.

"This is sometimes called the 'efficacy-effectiveness gap' and is not really surprising, because clinical trials are usually done in ideal conditions, whereas community practice represents real-world conditions and the patients are generally sicker and have comorbidities," he told Medscape Medical News.

He added that once patients have responded to several weeks of ketamine treatments, efforts are made to help them shift to other forms of management.


"For those patients who do well following a series of four to six ketamine infusions, we initially try and keep them well using a strategy that does not involve repeated use of ketamine," said Wilkinson.


Concerns Remain

Despite the encouraging improvements in depression that have been reported, the increased popularity of ketamine without long-term safety or efficacy data has raised considerable concerns, as reflected in aconsensus statement issued by an American Psychiatric Association Task Force in 2017.

Wilkinson said he shares the task force's concerns.

"Ketamine has tremendous potential, but this needs to be tempered with the potential risks. There needs to be a higher level of regulation than currently exists," he said.

"Ketamine is very safe in the short term, but we need better long-term data, because the risks of long-term adverse effects with repeated use are not theoretical," Wilkinson added.

"We know that too much ketamine is not good for the brain or bladder. We just don't know how much is too much," he said.

Dr Niciu has disclosed no relevant financial relationships. The senior author of the study is a coinventor on a patent for the use of ketamine and its metabolites in the treatment of major depression. Although he assigned his rights in the patent to the US Government, he will share a percentage of any royalties that may be received. Wilkinson has received funding, administered through Yale University, from Janssen to conduct clinical trials with esketamine. He has also received consulting fees of less than $5000 from Janssen.

Anxiety and Depression Association of America (ADAA) Conference 2018. Session 341R, presented April 7, 2018.

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