Dissociation found to mediate ketamine’s antidepressive effects

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight