This paper (2020) aimed to review the relationship between ketamine's anti-depressant effect and its subjective effects and found that they were correlated in some studies (1/3 studies).
Objective
The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD).
Methods
Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports.
Results
Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS.
Conclusions
Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Bouso, J. C., Pedrero-Pérez, E. J., Gandy, S. · Human Psychopharmacology (2016)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Garcia-Romeu, A., Kersgaard, B., Addy, P. H. · Experimental and Clinical Psychopharmacology (2016)
Mathai and colleagues frame ketamine as an N‑methyl‑D‑aspartate receptor (NMDAR) antagonist with rapid antidepressant effects that are hypothesised to arise from modulation of glutamate transmission, AMPA receptor potentiation and downstream neuroplastic changes. The introduction notes ketamine's broader pharmacology, neuroimaging findings, and historical links to psychedelic research; it highlights that ketamine can occasion pronounced alterations of consciousness that resemble, in some respects, experiences induced by serotonergic psychedelics. The authors point out that while dissociative and psychotomimetic effects are routinely measured in ketamine trials (often as adverse events), it remains unclear whether and how these subjective states relate to antidepressant benefit. This systematic review therefore set out to examine empirical evidence for a relationship between single‑dose ketamine‑induced subjective experiences and subsequent change in depression scores in adults with Major Depressive Disorder (MDD). Specifically, the investigators sought studies that measured subjective effects with validated psychometric scales (for example the Clinician‑Administered Dissociative States Scale, CADSS; the Brief Psychiatric Rating Scale, BPRS; and the 5‑Dimensional Altered States of Consciousness Rating Scale, 5D‑ASC) and statistically correlated those measures with depression outcomes following a single ketamine exposure. The goal was to clarify whether hallucinogenic or dissociative states contribute meaningfully to ketamine’s antidepressant mechanism or clinical effect.
The review followed PRISMA recommendations. Two reviewers performed searches of PsycINFO, Embase and PubMed for peer‑reviewed articles dated from 1 January 2000 to 31 May 2019. Search terms combined ketamine/esketamine with a broad set of terms capturing mystical, psychedelic, psychotomimetic and altered‑states constructs, plus depression‑related terms. Inclusion criteria required studies of adults diagnosed with MDD who received ketamine, with validated measures of depressive symptoms collected at regular intervals after administration, validated measures of subjective state collected on the day of dosing, and a reported statistical correlation between the subjective‑state measure and post‑injection depression scores. Studies limited to bipolar depression or without a single‑dose phase (i.e. only repeated dosing with no single‑dose data) were excluded. Only human, English‑language studies were eligible. Database searches initially yielded 554 records plus two cross‑references; after deduplication and screening 8 studies met the inclusion criteria. Two reviewers independently extracted data using a pre‑piloted form, resolving discrepancies by discussion. The investigators summarised study characteristics including sample age ranges, medication washout practices, ketamine route/doses and infusion durations. All included studies measured depression primarily with the Montgomery‑Åsberg Depression Rating Scale (MADRS) or versions of the Hamilton Depression Rating Scale (HAM‑D); secondary measures in some studies included the Beck Depression Inventory (BDI) or QIDS‑SR. Dissociative or psychotomimetic effects were assessed predominantly with the CADSS (a clinician‑rated scale for dissociative states) or the BPRS (a more general psychiatric symptom scale, often using a positive symptoms subscale). Two studies used additional measures, one using a Visual Analog Scale (VAS) and another the 5D‑ASC (a multi‑dimensional scale for altered states of consciousness). Timing of assessments typically captured dissociation within 20–240 minutes post‑infusion and depressive symptoms at multiple points up to 1 month post‑dose. The review also documented trial design features relevant to bias: six of eight studies were placebo‑controlled (five double‑blind, one single‑blind), two used midazolam as an active comparator, and study sample sizes and blinding integrity were recorded as potential quality concerns.
Eight studies were included. Participant ages ranged 18–70 years. Most trials used a single ketamine infusion; five studies administered intravenous 0.5 mg/kg, one used 0.54 mg/kg, one used a 0.1–1.0 mg/kg range, and one used intranasal 0.5 mg/kg. Infusion durations varied from 1 to 40 minutes. Three studies implemented a two‑week washout of other psychoactive medications, while five studies allowed maintenance of existing regimens. Subjective effects: In the five studies reporting CADSS data, ketamine produced marked dissociative effects with peak CADSS increases typically at 20–40 minutes post‑infusion. Dissociation showed a dose‑dependent pattern, with clear separation from midazolam beginning at 0.5 mg/kg and little effect at lower doses (0.1–0.2 mg/kg). For intranasal ketamine, the CADSS increase at 40 minutes was reported as 2.2 ± 3.7 versus 1.2 ± 3.3 for saline. BPRS findings were heterogeneous across studies: some reported transient increases in positive symptoms (unusual thought content, conceptual disorganisation, hallucinatory behaviour) in a minority of participants, while others observed no meaningful change or even decreases on total BPRS; intranasal BPRS increases were small (4.3 ± 0.7 versus 4.0 ± 0). One study using the 5D‑ASC documented large interindividual variability across subscales (for example vigilance reduction, dread of ego dissolution, oceanic boundlessness), with some patients meeting high thresholds on particular dimensions. Correlation between subjective effects and antidepressant response: Across the eight studies, three (37.5%) reported statistically significant associations between subjective measures and antidepressant outcomes. CADSS: of five CADSS studies, two found significant correlations. One study reported correlations between increased CADSS at 40 minutes and percent improvement in HAM‑D‑17 at 230 minutes (r = -0.35, p = 0.007) and Day 7 (r = -0.41, p = 0.01). Another study found that change in CADSS during infusion correlated with MADRS response at 24 hours (Pearson r = -0.46, p = 0.03). These coefficients indicate moderately negative linear relationships (greater dissociation associated with greater antidepressant improvement), with the dissociation measures explaining up to about 21% of variance in response. Three CADSS studies reported no significant correlations; one large analysis (n = 94 for some comparisons) found non‑significant correlations (for example r = -0.19, n = 94 at Day 1 and r = -0.13, n = 92 at Day 3) and an intranasal study reported no association. BPRS: six studies included BPRS data and five reported correlations. Only one study demonstrated a significant correlation: increases in total BPRS score correlated with MADRS at Day 7 (r = -0.40, p = 0.04), with trends at Day 1 and Day 4. That finding implies BPRS change accounted for about 16% of variance in antidepressant response in that sample. Other BPRS analyses showed no significant correlations (one reported R2 < 0.05, p > 0.65) or only non‑significant trends. 5D‑ASC: the single study that reported 5D‑ASC data did not find a significant correlation with MADRS percentage change on the day of treatment; full statistical details were not presented. Study quality and bias: sample sizes were generally small (median sample size for correlative analyses = 20; mean = 37.6 ± 41.3). Six of eight studies were placebo‑controlled and five were double‑blind; two studies used midazolam as an active placebo (reported doses 0.03 and 0.045 mg/kg). The reviewers noted potential unblinding risk given ketamine’s perceivable psychoactive effects and heterogeneity across measurement timing and scale use, which limited opportunities for quantitative meta‑analysis.
The investigators interpret the evidence as providing limited support for an association between ketamine‑induced subjective states and antidepressant response: three of eight studies (37.5%) reported weak to moderate correlations, and these three comprised a substantial portion of the pooled sample. When present, correlations were moderate and dissociation or psychotomimetic change accounted for a minority of variance in antidepressant outcome (reported estimates in correlated studies ranged roughly 12–21%). The authors emphasise that most included trials did not comprehensively examine correlations across all timepoints, potentially missing critical windows for detecting associations. Mathai and colleagues discuss measurement limitations as a central issue. They note that commonly used scales such as the CADSS and BPRS were developed for other clinical contexts (CADSS for PTSD‑related dissociation, BPRS for broad psychiatric symptom change) and may incompletely capture the phenomenology of ketamine‑induced altered states. One cited analysis suggested the depersonalisation subscale of CADSS related most closely to antidepressant response, but qualitative data indicate broader psychological changes are not well measured. The authors suggest that scales specifically designed for acute hallucinogenic effects (for example measures capturing oceanic boundlessness, ego dissolution or mystical‑type experiences) might better characterise subjective phenomena relevant to therapeutic response. The discussion places these findings alongside other clinical observations: attempts to develop NMDA‑modulating antidepressants with reduced dissociative effects (for example memantine, lanicemine) have not replicated ketamine’s efficacy, implying dissociative or psychoactive effects may be relevant; conversely, some pharmacological data indicate dissociation and antidepressant actions can be dissociated (for example naltrexone blocking antidepressant but not dissociative effects in one report) and repeated‑dose esketamine trials show antidepressant effects persist despite attenuation of dissociation over time. The authors therefore state that dissociation may be one of several contributors to ketamine’s effect but does not appear to account for the majority of treatment variance. Key limitations acknowledged include the small number of eligible studies, heterogeneous measures and timing, generally small sample sizes that precluded a robust quantitative meta‑analysis, potential unblinding across trials, and possible publication or reporting bias if negative correlations were not reported in some studies. The authors recommend individual participant data meta‑analysis to increase power and harmonise analyses, improved measurement tools tailored to ketamine’s phenomenology, and further research into whether therapeutic frameworks that facilitate meaningful subjective experiences could enhance and prolong antidepressant effects. They caution clinicians to consider expectancy effects and to recognise that dissociation is common in clinical practice (noting esketamine label‑reported dissociation rates of 61–75% as presented in the paper) and that the clinical relevance of subjective experiences requires clearer empirical characterisation.
Ketamine is a high-affinity N-methyl-D-aspartate receptor (NMDAR) antagonist with antidepressant effects thought to emerge from modulation of glutamate neurotransmissionand αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation. Ketamine has additional activity on opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters. Downstream influences on neurotrophic signaling cascades and neuroplasticityand functional changes in assorted neural networkshave also been implicated in ketamine's mechanism of effect. Neuroimaging studies have shown that ketamine reduces brain activation in regions associated with self-monitoring, increases activity in regions associated with emotional blunting, and increases neural activity in reward processing areas. Another arc of ketamine investigation dates back to the mid 20th century era of psychedelic research. Though primarily conceptualized as a dissociative anesthetic, ketamine has also been classified by some as a hallucinogenagents that function by various mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. There is converging evidence that the psychedelic effects of classic hallucinogens are mediated in part by activity at 5HT-2A receptorsthough also by a glutamatergic pathway, to some extent, which may be shared with ketamine. Though formal investigation into the phenomenology of subjective ketamine experience has been limited, there is some evidence to suggest that ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics. Preliminary clinical data from studies in addiction suggests that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors and beliefs related to abstinence from drugs and alcohol. Furthermore, dose-related mysticaland psychedelic-type experiences in substance-dependent patients have also been found to mediate the effects of ketamine on parameters such as motivation to quit, relapse, drug craving, and emotional attitudes toward abstinence in cocaine-dependent research volunteers.. Although it remains unclear how atypical states of consciousness are implicated in ketamine's antidepressant potential, other studies of ketamine, MDMA, and psilocybinhave provided impetus for this question with significant treatment implications. Research in this area is challenged by phenomenological and epistemic limitations in establishing a standardized methodology and measuring the subjective hallucinogenic experience. Some researchers posit that the quality of ineffabilityhaving to do with ideas incapable of being expressed with wordsis in fact a key aspect of intense psychedelic and mystical experience. Other limitations include that acute intoxication may interfere with real-time assessment or that purposeful introspection may interfere with the experience, typically addressed by collection of retrospective data, and also that drug-facilitated subjective experiences introduce experimental challenges such as potential unblinding of subjects. Many scales and structured interview techniques have been employed to quantify various aspects of subjective experience in psychedelic experience, however these have been minimally explored in the study of ketamine. Other scales, such as the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) are widely administered to measure ketamine's dissociative and psychotomimetic effects. These scales are used to capture tolerability data, as dissociation is traditionally considered an adverse drug effect, and provide some initial direction for understanding the nature and potential value of ketamine's psychoactive properties. To our knowledge, data from these scales have not been systematically analyzed to understand their potential contribution to antidepressant effects. Here we conduct a systematic review of how ketamine's hallucinogenic effects correlate with observed depression rating in the treatment of patients with Major Depressive Disorder (MDD). A strong relationship could optimize the therapeutic potential of ketamine by providing this treatment in an environment that facilitates these hallucinogenic and dissociative effects, as has been described with MDMA and psilocybin.
This review follows recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers conducted a systematic literature search in PsycINFO, Embase, and PubMed electronic databases for peer-reviewed journal articles from January 01, 2000 to May 31st, 2019. Search terms were combined using logic gates to produce a single query: (((ketamine) OR esketamine)) ANDOR mystical) OR psychedelic) OR psychotomimetic) OR altered states of consciousness) OR oceanic boundlessness) OR 5D-ASC) OR hallucinogen rating scale) OR phenomenology of consciousness inventory) OR hood's mysticism scale) OR mystical experience questionnaire) OR clinician administered dissociative symptoms scale) OR CADSS) OR BPRS) OR Brief Psychiatric Rating Scale) OR peak experience)) AND ((depression) OR depressive disorder). Studies eligible for inclusion in the review met the following criteria: 1. Patients were diagnosed with MDD at the time of the study; 2. Patients received ketamine; 3. MDD symptoms were measured with a validated scale at regular intervals after ketamine use; 4. Subjective changes in mental state were measured with a validated scale at regular intervals on the day of ketamine administration; 5. Post-injection MDD symptoms were statistically correlated with data capturing subjective changes in mental state. Studies that utilized a repeated dosing schedule without a single-dose phase were excluded. Studies that included only patients with bipolar depression were excluded to narrow the scope of the study, given existing differences in the understanding and treatment of unipolar versus bipolar depression. Eligible studies included human, English-language studies only, with no restrictions placed on participant age or study location.
Database searches yielded 554 records. Two additional studies were identified through cross-reference. A total of 343 duplicate records were removed. Two reviewers screened 213 records and identified 10 relevant articles. Of these articles, 3 records analyzed identical data; 2 of these records were removed. Ultimately, 8 studies were included in the review (Fig.). Data from eligible studies was independently extracted by two reviewers using a pre-piloted collection form. Discrepancies regarding article eligibility and data collection were resolved internally by discussion.
All patients in included studies were adults ranging from 18 to 70 years of age. Patients underwent a two-week washout period of all psychoactive drugs in three studies. In five studies, patients maintained their existing medication regimens. Intravenous infusions of 0.5 mg/kg were administered in five studies, and 0.54 mg/kg in one study. A single study used doses ranging from 0.1 to 1.0 mg/kg. Intranasal ketamine was administered at 0.5 mg/kg in one study. Most studies employed a single ketamine infusion, with the exception of a single study that repeated infusion after 1 week. Infusion duration ranged from 1 to 40 min across included studies.
All studies measured depression using the Montgomery-Asberg Depression Rating Scale (MADRS) or versions of the Hamilton Depression Rating Scale (HAM-D). BDI (Beck Depression Inventory) or QIDS-SR (Quick Inventory of Depressive Symptomatology Self-Report) were used as secondary depression rating scales in two studies. Dissociation was measured by CADSS or BPRS in all studies. Two studies included secondary dissociation scales, the Visual Analog Scale (VAS) or the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). All but two studiesmeasured depressive symptoms shortly (<230 min) after injection. Depression measurements were recorded daily, and then at weekly or bimonthly intervals. Measurements were terminated 3 days, 7 days, or 1 month post-injection. All studies measured dissociation in short (20-40 min) intervals up to 4 h post-infusion. Study characteristics are summarized in Table.
In all five studies that measured CADSS, ketamine produced marked dissociative effects. At 0.5 mg/kg, significant dissociation emerged at 20to 40minutes after intravenous administration. The dissociative effects of ketamine followed a dose-dependent relationship, with significant separation from midazolam as active placebo beginning at a dose of 0.5 mg/kg and not evident at lower ketamine doses of 0.1 mg/kg and 0.2 mg/kg.) also found that a 0.5 mg/kg dose of ketamine was associated with greater dissociation than midazolam, as measured immediately after 40 min infusion, with scores returning to baseline levels by two hours post-infusion. For intranasal ketamine, increases in CADSS scores were also most prominent at 40 min, with an increase of 2.2 ± 3.7 for patients who received 50 mg ketamine compared to 1.2 ± 3.3 in those who received placebo saline. BPRS: BPRS findings were heterogeneous across studies. Of note, studies differed in their use of the BPRS total scale, the BPRS positive symptoms subscale (focusing on symptoms of unusual thought content, conceptual disorganization, hallucinatory behavior, and grandiosity), or both.found that ketamine infusion produced significantly greater total BPRS scores, with evident increases in positive symptoms that did not translate to statistical significance. In contrast,found that ketamine significantly decreased total BPRS scores at 60, 80, 110, and 210 min, though no difference was found in positive symptom subscale scores at any time points between treatments.found a small increase in BPRS positive symptoms in 4 out of 10 patients that occurred 40 to 80 min after ketamine infusion and resolved thereafter.) also found that ketamine significantly increased BPRS positive symptoms at 40 min after administration. For intranasal ketamine, increases in total BPRS scores were marginal at 40 min, with an increase of 4.3 ± 0.7 for patients who received 50 mg ketamine compared to 4.0 ± 0 in those who received placebo saline. Other Subjective Measures: One study) measured subjective experiences of altered states of consciousness using the 5D-ASC and found large interindividual variability: 6/7 patients experienced "vigilance reduction" and "dread of ego dissolution" at greater than 50% of the scale maximum; three patients met this criteria for "oceanic boundlessness," one met criteria for "visionary restructuralization," and one for "auditory hallucinations."
CADSS: Five studies explored correlations between CADSS scores and antidepressant responses, with significant variability between studies.did not present this particular data but commented that peak changes in CADSS scores did not correlate with HAM-D-25 scores at any time point (HAM-D-25 was measured at baseline, 60 min, 180 min, 24 h, 48 h, 72 h, 5 days and 7 days after each infusion).found no statistically significant correlations between CADSS scores at 40 min after the infusion and HAM-D-6 scores at day 1 (r = -0.19; n = 94) and day 3 (r = =-0.13; n = 92). This study did not comment on other combinations of CADSS/HAM-D-6 timepoints or differences in correlations between the various doses of ketamine that were given.found that correlations were significant between increased CADSS at 40 min and percent improvement in HAM-D-17 at 230 min (r = -0.35, p = =0.007) and Day 7 (r = -0.41, p = =0.01), but not Day 1 (r = -0.21, p = =0.18). The study authors additionally commented that dissociation explained only a fraction of the variance in HAM-D-17 scores.examined correlations between CADSS and antidepressant response for a subgroup of participants in their singledose phase of study: changes in CADSS score during the ketamine infusion were significantly correlated with MADRS response at 24 h postinfusion (Pearson's r = -0.46, p = =0.03); CADSS score was measured immediately after administration of 0.5 mg/kg of ketamine that was delivered over a 40-minute time period. In the one study that involved intranasal ketamine, no relationship between ketamine-associated changes in dissociative symptoms and antidepressant response was found (p < 0.05). Among ketamine responders, the increase in CADSS score at 40 min was 1.75 ± 4.17 compared to 1.09 ± 1.76 in ketamine non-responders. To summarize these findings, two of five studies found significant correlation between increased CADSS scores at 40 min and antidepressant responses at various timepoints, including 230 min, 24 h, and seven days after ketamine infusion. The correlation coefficients from these two studies suggest moderately negative linear relationships, with change in CADSS score explaining no greater than 21% of the variance in antidepressant response in the included samples. There were some differences between these two studies, asfound that dissociation correlated with changes in MADRS scores 24 h after ketamine infusion, whilefound correlations with the HAM-D-17 at timepoints of 230 min and seven days, instead. Of note,analyzed data for 108 subjects, representing the largest sample size of all studies included in this review. For the remaining three studies without significant findings, notable characteristics include smaller sample sizes, varying route of administration (i.e. intranasal rather than intravenous delivery), and/or uncertainty as to whether statistical comparisons were completed across all possible score timepoints. BPRS: Six studies included BPRS measurements, although correlations with depression scores were presented in five.found a trend that did not achieve statistical significance suggesting an inverse association between peak BPRS-positive symptoms and MADRS percentage changes on Day 0. It is unclear if MADRS data beyond Day 0 were included in analysis.did not find significant correlation between either BPRS-total or BPRS-positive symptoms at 40 min and HAM-D-17 percentage changes at any timepoint in the study.found that changes in BPRStotal scores did not correlate with percent decreases observed in HAM-D-25 scores (R 2 < 0.05, p > 0.65), although it is unclear if these comparisons were done across all timepoints.found a significant correlation between increases in BPRS-total score and the MADRS scores at Day 7 (r = =-0.40, p = =0.04) with a trend toward significance at Day 1 (r = =-0.37, p = =0.06) and Day 4 (r = =-0.36, p < 0.07) when using a dose of 0.54 mg/kg over 30 min. No significant correlations were demonstrated when the same analyses were applied to BPRS subscales. For intranasal ketamine, no relationship between ketamine-associated changes in BPRS symptoms and antidepressant response was found (p < 0.05). In totality, only one of six studiesdemonstrated a significant correlation between increased BPRS scores and antidepressant response, which was evident when comparing BPRS-total scores and MADRS score at Day 7. The correlation coefficient from this study suggests a moderately negative linear relationship, with change in BPRS score explaining 16% of the variance in antidepressant response in the included sample. Earlier timepoints in this study also trended toward significance. Another studyfound a similar trend for increased BPRS-positive symptoms and antidepressant response during the day of ketamine administration. For several of the included studies, it was unclear if comparisons were done across all score timepoints. Other Subjective Measures: One studylooked at correlations between score changes on the 5D-ASC and MADRS. Although statistical data for this analysis was not presented in the text of the manuscript, the authors comment that no significant correlation was observed between 5D-ASC dimensions and MADRS percentage change on Day 0 (day of ketamine treatment). MADRS scores were collected at various other timepoints of the study, up until Day 29, though were not mentioned in the context of a correlative analysis.
Study populations were generally small; the median sample size used in correlative analysis was 20, with a mean of 37.6 ± 41.3. Six of eight studies were placebo-controlledtwo of these placebo-controlled studies used an active placebo of midazolam at doses of 0.03 mg/kg
Characteristics of studies included in a systematic review of ketamine's dissociative effects and depression scores.) 123-129and 0.045 mg/kgwhile the remainder used placebo saline. Of the six studies, five were completed under double-blind conditions and one under single-blind.conducted an open non-controlled study, andpresented a compiled analysis of three different studies: two of these examined the effects of ketamine under open-label conditions, and the other utilized a double-blind condition with placebo saline alongside ketamine. One risk of bias in ketamine trials is potential unblinding due to the profound psychoactive effects of ketamine. Only one study used a control (midazolam) to mitigate this effect. Additionally, one studyincluded patients with bipolar-depression in their study, perhaps limiting the validity of findings that may differ between unipolar and bipolar depression.
A systematic literature review of the relationship between the antidepressant and dissociative or hallucinogenic effects of ketamine found that three of 8 (37.5%) qualified studies supported a weak to moderatedegree of association. The CADSS, BPRS, and the 5D-ASC assessed hallucinogenic effects, and two of five CADSS studies (40%) found significant correlations, one of six BPRS studies (16.6%) demonstrated correlations, and one study using the 5D-ASC found no association with changes in depression scores. Of note, the three studies which support an association between dissociation and antidepressant effects represent three of the four largest included studies and approximately 55% of the pooled sample. In studies demonstrating a correlation, changes in BPRS and CADSS scores were responsible for 12-21% of the variance in antidepressant response. Several of the included studies did not provide correlations across all possible time-point scores, and thereby may have missed critical times for detecting such correlations. Overall, the incidence of dissociation appears to be common, with the package insert for esketamine, the S(+) enantiomer of ketamine, indicating that dissociation occurs in 61 to 75% of treated patients (SPRAVATOTM (esketamine) nasal spray, CIII Highlights of Prescribing Information, 2019). Moreover, another recent reviewconsiders strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of depression. However, greater intra-fusion dissociation as measured by the CADDS is one of the strongest predictors of extended antidepressant response to ketamine. In fact, pharmacologic strategies to develop alternative NMDA receptor modulating agents with fewer dissociative and psychotomimetic effects, such as memantine and lanicemine, have failed to show comparable antidepressant efficacy. These data need to be reconciled with other preliminary findings, for instance that naltrexone blocks antidepressant but not dissociative effects when co-administered with ketamine, and recent studies of repeated-dose esketamine, indicating that antidepressant effects persist in spite of attenuation of dissociative effects with time and that dissociation does not account for a significant proportion of treatment effect, based on the results of a limited (n = 3) mediation analysis. Our findings also suggest that even when significantly correlated with antidepressant response, typical measurements of dissociative experience still incompletely capture variance in treatment outcome. Additional clarification of the relevance of dissociation seems essential not only for clinicians and researchers working with ketamine but also for patients, since other psychedelic agents such as MDMA and psilocybin are also showing significant and rapid antidepressant effects, but are being developed within treatment protocols that take these effects into consideration. In framing aspects of treatment such as dissociation with patients, clinicians should note that treatment expectancies significantly mediate outcomes in both psychotherapy and psychopharmacotherapy. The measurement of dissociation also needs improved tools, since the CADSS does not fully capture ketamine-induced changes in dissociation, thought-process, and broader alterations in consciousness. One study that analyzed CADSS data in ketamine treatment found that the depersonalization ("detachment from self") subscale was most closely related to antidepressant response, but also found that other psychological activity was inadequately captured by the CADSS, based on qualitative analysis of patient narratives. The CADSS was initially developed and validated for use in patients with combat-related posttraumatic stress disorder (PTSD) and high levels of comorbid dissociative disorder. Dissociation of this kind may be phenomenologically different from the dissociation experienced under the influence of ketamine or these other dissociative agents. That is to say, it is unclear how similar drug-induced dissociation is to dissociation of psychological disorders like PTSD. The BPRS, originally developed to provide rapid and non-specific assessment of changes in clinical status, is also limited for capturing psychedelic effects. The positive symptoms subscale of the BPRS, as currently used in ketamine research, functions to monitor psychotomimetic changes and dissociation as an adverse drug effect. Rating scales specifically designed to measure acute effects of hallucinogens may prove more useful in understanding ketamine-induced experience. Some preliminary work with alternative scales suggests that it may be less the individual degree of experienced dissociation or type of dissociative experience, but rather the absence of negative subjective or emotional experience that predicts treatment response to ketamine. The short duration of ketamine's antidepressant effect, which peaks at 24 h post-infusion and generally subsides by 72 h, has led to repeated ketamine infusions to extend time-to-relapse and increase rates of antidepressant response. If ketamine's therapeutic effect is indeed mediated by psychoactive experience, repeated dosing of ketamine may improve outcomes by increasing opportunities for personally meaningful experiences to occur. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and duration, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk. Our review has several limitations including few relevant studies, small sample sizes within some studies, and an inability to conduct a robust meta-analysis, due to the limited availability of data and heterogeneity in these 8 studies. Some investigations were also underpowered to detect clinically significant effects. Maintaining the single or double blinding of all the studies may not be valid, as ketamine elicits perceptible shifts in conscious experience when compared to inactive placebo, and such experiences could fairly be considered sideeffects or epiphenomena rather than representative of ketamine's mechanism of action. Further, other studies that examined the relationship between the antidepressant and dissociative effects of ketamine and did not find a correlation may not have reported on this parameter, leading to exclusion in our analysis and thereby introducing an additional degree of bias. A critical step in moving forward would include metaanalysis of individual data from studies that have examined both dissociative and antidepressant data, in an effort to increase statistical power and account for inconsistencies between studies. However, the findings presented here provide support for further consideration of ketamine-induced states of consciousness and investigation into the relevance of these states in treatment outcomes.
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