Discussion
TRD, dissociative amnesia, ideation, nausea, anxiety, pain, amnesia, Dissociative, MDD, depression, dissociative depersonalization
DISORDER, REMISSION, DETACHMENT, DISORDERS
The present findings advance our understanding of the role of ketamine-induced ASCs in mediating neural changes in the brain’s affective circuitry. In our placebo-controlled, within-participant design which examined nonclinical participants, we conducted multi-modal measurements of dissociation and other ASCs as well as emotional-faces-evoked affective circuit activity before, during, and/or within ~2 h of racemic intravenous (IV) ketamine (0.05 mg/kg or 0.5 mg/kg) or placebo infusion. We found that ketamine-induced acute, dose-dependent increases in ASCs—including dissociative depersonalization, derealization, and a blissful state—which we hypothesized would alleviate negative affective states. Ketamine also induced dose-dependent increases in acute ASCs associated with negative affect, including dissociative amnesia, anxiety, and impaired control and cognition. There was no effect of placebo on these measures. These findings align with previous work in the mechanistic literature that showed significant increases in dissociation in response to ketamine (e.g., refs. A key insight from this trial is that the acute effect of subanesthetic ketamine on the brain’s negative affect circuitry may be specific to and dependent on the level of specific aspects of dissociation and other ASCs. We measured reactivity within affective circuitry using a well-established facial emotion task, focusing on the anterior insula, amygdala, and ACC. We found that compared to lower dissociative depersonalization, higher dissociative depersonalization mediated reduced right anterior insula activity in response to negative emotional stimuli, whereas higher dissociative amnesia mediated an increase in task-evoked right anterior insula reactivity. These findings suggest that at least two mechanisms of action contribute to the acute dissociative effects of ketamine on the brain’s affective circuitry. Specifically, induction of the depersonalization aspect of dissociation might be an essential ingredient in the mechanisms by which ketamine alleviates negative affective brain states. Ketamine’s effects on depersonalization, or the sensation of detaching from one’s body, might be accompanied by detachment from negative affective states of emotional pain including depressionOur mediation findings might help to account for potentially inconsistent findings across studies, methodologies, and healthy versus clinical participants. When we considered the group effects in our trial, without considering variability in different aspects of dissociation, ketamine induced an increase in the average threat-faces-evoked reactivity of the right anterior insula and right amygdala compared to placebo. The emotion task deployed in our trial is designed to evoke reactivity of these regions, including under drug conditions. Prior trials imaging facial emotion-evoked activity after two days post-ketamine have observed increases in amygdala for individuals with MDD, but decreases in the insula, and opposing patterns of change for healthy individualsLet’s examine the translational therapeutic implications of this study’s results. Dissociative effects induced by ketamine are known to commonly occur at therapeutic doses for TRD in over 70% of participants with IV ketamineWe found that the altered states of depersonalization and amnesia significantly mediated the effect of a therapeutic antidepressant dose of racemic IV ketamine (0.5 mg/kg) on threat-faces-evoked right anterior insula reactivity, while anxiety showed a marginal mediation in the same direction as the amnesia. The states have been previously found to relate to longer-term antidepressant response. Depersonalization assessed by the CADSS, but not overall dissociation, has been found to predict antidepressant response to racemic IV ketamineWhile the dissociative effects of ketamine have been most studied in the context of depression, our findings may have implications for other disorders for which ketamine is being studied and insula reactivity has been shown to play a key role, including SUDs. A qualitative study of experiences while undergoing three ketamine infusions for treating alcohol use disorder found that participants reported that dissociation was important to changing their relationship with alcohol and that the infusion experience decreased their motivation to drink to relieve negative emotional statesThese findings may also be relevant for identifying who will respond to ketamine within the first session. Response and remission rates for IV ketamine for depression are 53.6% and 28.9% in a real-world sample, and some individuals have worsening of depression (8%) and suicidal ideation (6%) with ketamine treatmentLet’s examine the reverse translational implications of the current study’s results. Future reverse translational work in mouse models will be essential for developing a better understanding of the causal relationships between dissociation as measured by behavioral paradigms, such as the one developed by Deisseroth and colleaguesThe insights derived from this study must be considered within the context of the study’s limitations. First, because our focus was on multi-measurement, multi-domain assessment of ketamine’s acute effects, the sample size was limited and not intended to provide a basis for making broader group average inferences. It will be essential to conduct studies designed to replicate and expand these findings. Second, our multi-domain methodology necessarily relies on the administration of a series of assessments at multiple time points within each IV session. While we made every effort to administer assessments within the exact same timing for each participant, this was not always possible due to the need to first address side effects such as nausea. The third limitation relates to the temporal sequence of our mediation models, which was selected based on the order of our measures. Clearly, a change in brain state must have occurred in order for dissociation and other ASCs to occur. It is not clear from our current design whether this brain state is the same as the one we measured during our functional neuroimaging session. Thus, we cannot conclude that depersonalization and dissociative amnesia caused the differential changes in task-evoked anterior insula that we observed. This question may be examined in designs that use more frequent repeated sampling with higher temporal-resolution neuroimaging tools. Fourth, because ketamine has an impact across multiple biological systems, we recognize that there might be additional mediators on the activation of the insula in response to threat, including physiological measures such as heart rate and blood pressuresTo our knowledge, this work provides an initial demonstration that acute ketamine-induced changes in anterior insula reactivity to negative emotional stimuli depend upon specific aspects of dissociative experiences and other ASCs. These findings shed light on the neurobiological mechanisms that underlie ketamine’s ability to both acutely relieve negative affective states and induce them in nonclinical participants. Furthermore, if these results are extended to patients with depression, they should advance scientific understanding about how aspects of intra-infusion ASCs might predict depression response—results that might help inform more personalized treatment interventions.