Clinician-Administered Dissociative States Scale Research Articles

Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study.

While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD). Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾ 24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾ 50% MADRS score reduction) was the primary outcome. By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days-2 weeks; effect size (ES) = 1.08-1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation. Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.

Enantioselective inhibition of d-serine transport by (S)-ketamine.

Patients with major depressive disorder receiving racemic ketamine, (R,S)-ketamine, experience transient increases in Clinician-Administered Dissociative States Scale scores and a coincident drop in plasma d-serine levels. The results suggest that (R,S)-ketamine produces an immediate, concentration-dependent pharmacological effect on d-serine plasma concentrations. One potential source of this effect is (R,S)-ketamine-induced inhibition of the transporter ASCT2, which regulates intracellular d-serine concentrations. In this study, we tested this hypothesis by examining the effect of (S)- and (R)-ketamine on ASCT2-mediated transport of d-serine in PC-12 and 1321N1 cells and primary neuronal cells in culture. Intracellular and extracellular d-serine levels were determined using capillary electrophoresis-laser-induced fluorescence and liquid chromatography-mass spectrometry respectively. Expression of ASCT2, Asc-1 and serine racemase was determined utilizing Western blotting. (S)-Ketamine produced a concentration-dependent increase in intracellular d-serine and reduced extracellular d-serine accumulation. In contrast, (R)-ketamine decreased both intracellular and extracellular d-serine levels. The ASCT2 inhibitor, benzyl-d-serine (BDS), and ASCT2 gene knockdown mimicked the action of (S)-ketamine on d-serine in PC-12 cells, while the Asc-1 agonist d-isoleucine reduced intracellular d-serine and increased extracellular d-serine accumulation. This response to d-isoleucine was not affected by BDS or (S)-ketamine. Primary cultures of rat neuronal cells expressed ASCT2 and were responsive to (S)-ketamine and BDS. (S)- and (R)-ketamine increased the expression of monomeric serine racemase in all the cells studied, with (S)-ketamine having the greatest effect. (S)-Ketamine decreased cellular export of d-serine via selective inhibition of ASCT2, and this could represent a possible source of dissociative effects observed with (R,S)-ketamine.

MDMA, cannabis, and cocaine produce acute dissociative symptoms

Some drugs of abuse may produce dissociative symptoms, but this aspect has been understudied. We explored the dissociative potential of three recreational drugs (3,4-methylenedioxymethamphetamine (MDMA), cannabis, and cocaine) during intoxication and compared their effects to literature reports of dissociative states in various samples. Two placebo-controlled studies were conducted. In Study 1 (N=16), participants received single doses of 25, 50, and 100mg of MDMA, and placebo. In Study 2 (N=21), cannabis (THC 300µg/kg), cocaine (HCl 300mg), and placebo were administered. Dissociative symptoms as measured with the Clinician-Administered Dissociative States Scale (CADSS) significantly increased under the influence of MDMA and cannabis. To a lesser extent, this was also true for cocaine. Dissociative symptoms following MDMA and cannabis largely exceeded those observed in schizophrenia patients, were comparable with those observed in Special Forces soldiers undergoing survival training, but were lower compared with ketamine-induced dissociation. Cocaine produced dissociative symptoms that were comparable with those observed in schizophrenia patients, but markedly less than those in Special Forces soldiers and ketamine users. Thus, MDMA and cannabis can produce dissociative symptoms that resemble dissociative pathology. The study of drug induced dissociation is important, because it may shed light on the mechanisms involved in dissociative psychopathology.

Safety and efficacy of ketamine infusion in late onset depression, and conversion to treatment response.

Byline: Shrikant. Srivastava, Radhey. Gangwar, Ambrish. Kumar Sir, Response rates to first line antidepressant therapy are abysmally low, and more so in older adults. Ketamine has been used successfully in treatment-resistant depression (TRD), and in nongeriatric population, with response rates at 24 and 72 h postinfusion being 25−85% and 14−72%, respectively.[sup][1] The postulated mechanism of action is through antagonism of N-methyl-D-aspartate receptors.[sup][2] A 65-year-old retired civil servant, living with her husband had fourth episode of depressive illness. In the last 3 years, the illness showed increasing resistance to antidepressant medication(s) with each additional episode. The first episode remitted with escitalopram (10 mg/day), the second episode required higher dosage of escitalopram (40 mg/day), and later, augmentation with amisulpride 25 mg/day, and the third episode remitted with duloxetine (up to 60 mg/day) (as she had relapsed while on escitalopram) and amisulpride 100 mg/day. In the Inter-episode period, the patient had attended all follow-up appointments and continued with prescribed medication. In this episode, she had failed treatment with duloxetine + amisulpride, agomelatine, and agomelatine + amisulpride, respectively. Informed consent was obtained from the patient. Ketamine infusion (0.5 mg/kg diluted in 100 ml of normal saline) was given over 40 min, under the supervision of consultant anesthetist (RSG). Ratings of mood (Hamilton rating scale for depression [HAMD])[sup][3] and side effects (Clinician Administered Dissociative States Scale)[sup][4] were undertaken on morning of the infusion, and 1, 2, and 4 h following infusions, and on in between days of the infusion [labelled as postinfusion days in Table 1]. Four days after the 4[sup]th infusion (HAMD = 10), the patient feeling very much improved subjectively, the ketamine infusions were discontinued, with the provision that further infusions may be required if the depressive symptoms recurred. Agomelatine 50 mg/day was continued through the infusion period and in the follow-up phase.{Table 1} Remission (HAMD The side effects reported with the infusions were − alteration of passage of time (infusion 3, hours 1 and 2) and mild gaps in memory (infusion 4, hour 2). …

Early initiation of alcohol or marijuana use and nonmedical use of prescription drugs

Early initiation of alcohol or marijuana use and nonmedical use of prescription drugs

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements. Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. clinicaltrials.gov Identifier: NCT00749203.

Temporal Order Assessment in Patients with Bipolar Disorder

Alterations in temporal perception accompany dissociative symptoms. However, the extent and frequency of these temporal symptoms have not been extensively studied in Bipolar Disorder (BD). The study was a prospective, repeated measures design of 21 patients with BD, conducted at Barwon Health in Geelong, Australia. The study combined questionnaires of mood and dissociative symptoms with a novel psychophysical method of assessing altered sub-second temporal performance. Participants observed a series of two flashed visual stimuli (duration 20ms, inter stimulus interval 60ms) while making rapid (saccadic) eye movements. The experimental paradigm resulted in a proportion of observations (47%) in which the perceptual ordering of the flashes was inverted in time. Dissociative symptoms, as measured by the Dissociative Experiences Scale, were common in this patient cohort. The proportion of inverted temporal judgments correlated with both dissociative symptom scores (Clinician Administered Dissociative States Scale, unreality subscale) and with the Young Mania Rating Scale score (in linear model). This study shows that measures of temporal perception correlate with mood alterations in BD. This finding is the first to find such associations with a sub-second timing task. The linkage between the symptoms of BD and testable measures of time perception, supports the case for psychophysical measures of dissociation having utility as biomarkers of disease state.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

BackgroundThe N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. MethodsData from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7. ResultsPearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. LimitationsSecondary data analysis, combined diagnostic groups, potential unblinding. ConclusionsAmong the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms

BackgroundPredominant dissociation in posttraumatic stress disorder (PTSD) is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms.ObjectiveThis study tested the hypothesis that PTSD patients with high dissociative symptoms will display increased event-related potential (ERP) amplitudes in early components (N1, P1) to threatening faces (angry, fearful), and reduced later ERP amplitudes (Vertex Positive Potential (VPP), P3) to happy faces compared to PTSD patients with low dissociative symptoms.MethodsThirty-nine civilians with PTSD were classified as high dissociative (n=16) or low dissociative (n=23) according to their responses on the Clinician Administered Dissociative States Scale. ERPs were recorded, whilst participants viewed emotional (happy, angry, fear) and neutral facial expressions in a passive viewing task.ResultsHigh dissociative PTSD patients displayed significantly increased N120 amplitude to the majority of facial expressions (neutral, happy, and angry) compared to low dissociative PTSD patients under conscious and preconscious conditions. The high dissociative PTSD group had significantly reduced VPP amplitude to happy faces in the conscious condition.ConclusionHigh dissociative PTSD patients displayed increased early (preconscious) cortical responses to emotional stimuli, and specific reductions to happy facial expressions in later (conscious), face-specific components compared to low dissociative PTSD patients. Dissociation in PTSD may act to increase initial pre-attentive processing of affective stimuli, and specifically reduce cortical reactivity to happy faces when consciously processing these stimuli.

Spontaneous and Deliberate Dissociative States in Military Personnel: Are Such States Helpful?

This study explored distinctions between spontaneous and deliberate dissociative states in 335 military personnel exposed to stressful survival training. Participants completed the Clinician-Administered Dissociative States Scale (CADSS) after a stressful mock-captivity event. They were also asked to indicate whether the dissociative experiences just happened (i.e., spontaneous), or whether they chose to have them happen (i.e., deliberate); and whether they appraised the dissociative experience as helpful (i.e., facilitative) or hurtful (i.e., debilitative) to their ability to cope with the stressful event. A majority (95.4%) endorsed dissociative states during stress. More than half (57.4%) described dissociative experiences as spontaneous, 13.0% as deliberate, and 29.5% endorsed neither. In Special Forces soldiers only, those who endorsed facilitative dissociation exhibited higher total CADSS scores than those who endorsed debilitative dissociation. Seventy-three percent of spontaneous dissociators described the experience as debilitative to coping with stress; conversely, 76% of deliberate dissociators said these experiences facilitated coping with stress. Individuals with prior trauma exposure tended to appraise dissociative states as more debilitative to coping. This research may enhance the fidelity of studies of dissociation constructs and may offer pivot points for prevention and treatment of stress-related disorders.

The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects

BackgroundInteractions between glutamatergic and endocannabinoid systems may contribute to schizophrenia, dissociative states, and other psychiatric conditions. Cannabidiol (CBD), a cannabinoid-1/2 (CB1/2) receptor weak partial agonist or antagonist, may play a role in the treatment of schizophrenia. ObjectiveThis study tested the hypothesis that CBD would attenuate the behavioral effects of the NMDA receptor antagonist, ketamine, in healthy human subjects. MethodsTen male healthy volunteers were evaluated twice in a randomized order. In both sessions they received ketamine (bolus of 0.26mg/kg/1min followed by IV infusion of 0.25mg/kg over 30min) preceded by either CBD (600mg) or placebo. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) and the CADSS (Clinician Administered Dissociative States Scale) at regular intervals from 30min before to 90min after ketamine administration. ResultsCBD significantly augmented the activating effects of ketamine, as measured by the activation subscales of the BPRS. However, CBD also showed a non-significant trend to reduce ketamine-induced depersonalization, as measured by the CADSS. ConclusionThese data describe a complex pattern of psychopharmacologic interactions between CBD and ketamine at the doses of each agent studied in this experiment.

Glutamate and the Neural Basis of the Subjective Effects of Ketamine

Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. Wellcome Trust Clinical Research Facility, Manchester, England. Thirty-three healthy, right-handed men were recruited by advertisements. In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

Frontal and occipital perfusion changes in dissociative identity disorder

The aim of the study was to investigate if there were any characteristics of regional cerebral blood flow (rCBF) in dissociative identity disorder. Twenty-one drug-free patients with dissociative identity disorder and nine healthy volunteers participated in the study. In addition to a clinical evaluation, dissociative psychopathology was assessed using the Structured Clinical Interview for DSM-IV Dissociative Disorders, the Dissociative Experiences Scale and the Clinician-Administered Dissociative States Scale. A semi-structured interview for borderline personality disorder, the Hamilton Depression Rating Scale, and the Childhood Trauma Questionnaire were also administered to all patients. Normal controls had to be without a history of childhood trauma and without any depressive or dissociative disorder. Regional cerebral blood flow (rCBF) was studied with single photon emission computed tomography (SPECT) with Tc99m-hexamethylpropylenamine (HMPAO) as a tracer. Compared with findings in the control group, the rCBF ratio was decreased among patients with dissociative identity disorder in the orbitofrontal region bilaterally. It was increased in median and superior frontal regions and occipital regions bilaterally. There was no significant correlation between rCBF ratios of the regions of interest and any of the psychopathology scale scores. An explanation for the neurophysiology of dissociative psychopathology has to invoke a comprehensive model of interaction between anterior and posterior brain regions.

Greater vulnerability to the amnestic effects of ketamine in males

Gender differences both in response to ketamine in animals and general cognitive functioning in humans have been observed and suggested to be related to modulatory effects of sex hormones on N-methyl-D: -aspartate receptor (NMDA-R) functioning. The current study aimed to determine whether there were gender differences in response to ketamine in humans. Behavioral data including positive and negative symptoms (Brief Psychiatric Rating Scale), perceptual alterations (Clinician-Administered Dissociative States Scale, CADSS), and "high" and "anxiety" states (Visual Analog Scale) from 295 subjects who participated in a total of 11 placebo-controlled ketamine studies were analyzed. In a subset of subjects, memory (Hopkins Verbal Learning Task: HVLT, n=108) and attention (continuous performance task, n=177) data were also analyzed. Male participants showed a greater performance decrement on the HVLT after ketamine administration compared to women. Men also reported a greater subjective sense of memory impairment on a CADSS subscale. No other gender differences in behavioral or cognitive measures were observed. Men showed a greater vulnerability to the amnestic effects of ketamine than women. Possible explanations of these findings are neuroanatomical and cognitive differences in processing of words in men and women and interactions between sex hormones and NMDA-R function.

Frontal Responses During Learning Predict Vulnerability to the Psychotogenic Effects of Ketamine

Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. Within-subject, randomized, placebo-controlled study. Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers

N-methyl-D: -aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience. The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion. Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation. At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels. This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.

Dissociation and Posttraumatic Stress 1 Year After the World Trade Center Disaster

We conducted a 1-year follow-up of an original mail survey of early reactions to the World Trade Center disaster. Of the 75 subjects originally surveyed, 58 (77%) responded. The survey included measures of dissociation (Dissociative Experiences Scale, Cambridge Depersonalization Scale, Clinician-Administered Dissociative States Scale), post-traumatic stress (Impact of Event Scale-Revised), social support (Interpersonal Support Evaluation List-short form), and a life quality measure (Quality of Life Enjoyment and Satisfaction Questionnaire-short form). We hypothesized that dissociative versus posttraumatic symptoms at follow-up could be dissected on the basis of early reactions. Responders and nonresponders did not differ in baseline characteristics. Exposure was not associated with dissociation or posttraumatic stress at follow-up. Of distress, dissociation, and posttraumatic stress at baseline, baseline dissociation was the strongest predictor of outcome dissociation while baseline posttraumatic stress was the strongest predictor of outcome posttraumatic stress. Of 4 peritraumatic distress factors generated in the original survey, "loss of control" and "guilt/shame" were significantly related to dissociation and posttraumatic stress at outcome, while "helplessness/anger" was only associated with posttraumatic stress at outcome. Lesser improvement in posttraumatic stress over the first year was significantly related to less social support and greater comorbid dissociation. Interim social support was associated with better life quality and fewer symptoms at outcome. There was evidence for partly independent pathways toward dissociation versus posttraumatic stress 1 year after the disaster. Feelings of guilt and shame, and persistent dissociation, were poor prognostic factors, while social support had a powerful ameliorating influence.

Effects of Ketamine on Anterior Cingulate Glutamate Metabolism in Healthy Humans: A 4-T Proton MRS Study

The authors' goal was to test in humans the hypothesis that N-methyl-d-aspartate receptor (NMDAR) antagonism results in increased cortical glutamate activity, as proposed by the NMDAR hypofunction model of schizophrenia. 4-T 1H proton magnetic resonance spectroscopy (1H-MRS) was used to acquire in vivo spectra from the bilateral anterior cingulate of 10 healthy subjects while they received a subanesthetic dose of either placebo or ketamine, an NMDAR antagonist. Assessments given before and after ketamine or placebo administration included the Brief Rating Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, the Clinician-Administered Dissociative States Scale, and the Stroop task. As predicted, there was a significant increase in anterior cingulate glutamine, a putative marker of glutamate neurotransmitter release, with ketamine administration. This increase was not related to schizophrenia-like positive or negative symptoms but was marginally related to Stroop performance. In humans as in animals, an acute hypofunctional NMDAR state is associated with increased glutamatergic activity in the anterior cingulate.

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine

Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

OBJECTIVE: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. METHOD: Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels. RESULTS: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. CONCLUSIONS: These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism.