Long-term follow-up of participants in ketamine clinical trials for mood disorders.

BACKGROUND: Participants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. METHODS: Participants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. RESULTS: Of the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LIMITATIONS: Low follow-up study participation rate; varying time since discharge. CONCLUSIONS: Participants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. CLINICAL TRIALS IDENTIFIER: NCT04877977.

Treatment of dissociative symptoms with opioid antagonists: a systematic review.

BACKGROUND: The clinical guidelines for the treatment of dissociation focus primarily on psychotherapy. However, different psychoactive drugs are used in clinical practice. The use of opioid antagonists has been proposed as a therapeutic option based on the theory that dissociation might be a phenomenon mediated by dysregulation of the endogenous opioid system. OBJECTIVE: To review and meta-analyse the available evidence on the efficacy of the opioid antagonists naltrexone, naloxone, and nalmefene as treatments for dissociative symptoms and disorders. METHOD: The PRISMA guidelines were followed, and this review was registered in Prospero with reference number CRD42021280976. The search was performed in the PubMed, Scopus, Web of Science, EMBASE, PsycINFO, and PubPsych databases. RESULTS: 1,798 citations were obtained. After removing duplicates and applying inclusion and exclusion criteria, we included 5 comparative studies with 9 dissociation measures that had included a total of 154 participants, of whom 134 had been treated with an opioid antagonist. The results of the meta-analysis showed a treatment effect for dissociation when using opioid antagonists [pooled d = 1.46 (95% CI: 0.62-2.31)]. However, the studies we included were very heterogeneous [Q = 66.89 (p < .001)] and there may have been publication bias. CONCLUSIONS: Although more research is needed and the results must be interpreted with caution because of the limited amount of data and heterogeneity in the studies and their methodological qualities, opioid antagonists (particularly naltrexone) are promising candidates for the treatment of dissociative symptoms and showed a moderate - large effect size in reducing these symptoms.

The results of the meta-analysis showed a treatment effect for dissociation when using opioid antagonists [pooled d = 1.46 (95% CI: 0.62­2.31)].The results must be interpreted with caution because of the limited amount of data and heterogeneity in the studies and their methodological qualities.Opioid antagonists (particularly naltrexone) are promising candidates for the treatment of dissociative symptoms and showed a moderate ­ large effect size in reducing these symptoms.

Remission of schizophrenia after an EMDR session.

We present a case study of the remission of a chemically resistant schizophrenia disorder after a single session of EMDR. Our patient had been followed-up for schizophrenia according to DSM5 criteria, since 4 years. During our subject's fourth hospitalization for major delirious decompensation, a single EMDR session, according to the standard protocol, resulted in a complete and total remission of the delirious disorder and the disorganization/dissociative syndrome in 8 weeks. This allowed us to interrupt the patient's antipsychotic treatment without relapse at 18 months. This case study allows us to highlight, as many authors have previously done, the necessity of researching the traumatic history of patients diagnosed with schizophrenia in order to provide therapies focused on traumatic dissociation. It also questions the relevance of our diagnostic criteria for schizophrenia and other dissociative disorders.

Presentamos un estudio de caso sobre la remisión de una esquizofrenia químicamente resistente tras una sola sesión de EMDR. Nuestro paciente había sido seguido por esquizofrenia según los criterios del DSM 5, desde hace 4 años. Durante la cuarta hospitalización de nuestro sujeto, por descompensación delirante mayor, una única sesión de EMDR según el protocolo estándar, dio lugar a una remisión completa y total del trastorno delirante y del síndrome de desorganización/disociativo en 8 semanas. Esto nos permitió interrumpir el tratamiento antipsicótico de la paciente sin recaídas a los 18 meses. Este estudio de caso nos permite destacar, como muchos autores han hecho anteriormente, la necesidad de investigar la historia traumática de los pacientes diagnosticados de esquizofrenia para ofrecer terapias centradas en la disociación traumática. También cuestiona la pertinencia de nuestros criterios diagnósticos para la esquizofrenia y otros trastornos disociativos.

The Clinician-Administered Dissociative States Scale (CADSS): Validation of the German Version.

The Clinician-Administered Dissociative States Scale (CADSS) is a structured clinical interview to assess state dissociation rated by clinicians. The current study aimed to validate the German version of CADSS by comparing it to the established self-report measures for dissociation and exploring its underlying factor structure. Severity of within-session state dissociation was assessed directly following a standard psychotherapy session in a trauma-exposed patient sample (N= 105; 81.9% female). Internal consistency, convergent validity with other dissociation measures, and the factorial structure of the instrument were analyzed. The German version exhibited excellent internal consistency (Cronbach's α = .94) and correlated significantly with self-report measures of state dissociation (r = .86) and trait dissociation (r = .77) indicative of high convergent validity. Exploratory factor analysis revealed a three-factor solution with the factors (1) Depersonalization/Derealization, (2) Identity Confusion/Alteration, and (3) Amnesia. Results support the CADSS as a useful instrument to assess state dissociation, conceptualized as a multidimensional construct, in clinical practice.

A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions.

BACKGROUND: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use. METHODS: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed. RESULTS: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001). LIMITATIONS: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population. CONCLUSIONS: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation.

Cardiovascular effects of repeated subanaesthetic ketamine infusion in depression.

BACKGROUND: Ketamine produces significant rapid-onset and robust antidepressant effects in patients with major depressive disorder. However, this drug also has transient cardiovascular stimulatory effects, and there are limited data about potential predictors of these cardiovascular effects. METHODS: A total of 135 patients with unipolar and bipolar depression received a total of 741 ketamine infusions (0.5 mg/kg over 40 min). Blood pressure and pulse were monitored every 10 min during the infusions and 30 min after the infusions. Depressive, psychotomimetic and dissociative symptom severity was assessed at baseline and 4 hours after each infusion. RESULTS: The maximum blood pressure and pulse values were observed at 30-40 min during infusions. The largest mean systolic/diastolic blood pressure increases were 7.4/6.0 mmHg, and the largest mean pulse increase was 1.9 beats per min. No significant change in blood pressure and pulse was found in the second to sixth infusions compared with the first infusion. Patients who were older (age⩾50 years), hypertensive and receiving infusions while exhibiting dissociative symptoms showed greater maximal changes in systolic and diastolic blood pressure than patients who were younger (age<50 years), normotensive and without dissociative symptoms (all p < 0.05). Hypertensive patients had less elevation of pulse than normotensive patients (p < 0.05). Ketamine dosage was positively correlated with changes in systolic and diastolic blood pressure (all p < 0.05). CONCLUSIONS: Blood pressure and pulse elevations following subanaesthetic ketamine infusions are transient and do not cause serious cardiovascular events. Older age, hypertension, large ketamine dosage and dissociative symptoms may predict increased ketamine-induced cardiovascular effects.

Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial.

BACKGROUND: Sub-anesthetic ketamine administration may be helpful for substance use disorders. Converging evidence suggests that the efficacy of ketamine for certain conditions may implicate a subset of its psychoactive effects. AIMS: The aim of this analysis is to evaluate whether the mystical-type effects of ketamine are critical for clinical efficacy in alcohol-dependent individuals. In this secondary analysis, we determine if a subset of the psychoactive effects of ketamine, the so-called mystical-type experience, mediates the effect of ketamine, when combined with motivational enhancement therapy, on at-risk drinking behavior in alcohol-dependent individuals interested in treatment. METHODS: Forty alcohol dependent adults were randomized to either a 52-minute infusion of ketamine or midazolam, which they received on a designated quit-day during the second week of a five-week motivational enhancement therapy regimen. Psychoactive effects were assessed following the infusion, and alcohol use was monitored for the subsequent 3 weeks at each twice-weekly visit. RESULTS: We found that ketamine leads to significantly greater mystical-type effects (by Hood Mysticism Scale) and dissociation (by Clinician Administered Dissociative States Scale) compared to the active control. Ketamine also led to significant reduction in at-risk drinking. The Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior. CONCLUSIONS: This trial adds evidence to the literature on the importance of mystical-type experiences in addiction treatment. Future research should continue to investigate the relationship between the psychoactive effects of psychedelic therapeutics and clinical outcomes for other substance use and mental health disorders.

The role of dissociation in ketamine's antidepressant effects.

Ketamine produces immediate antidepressant effects and has inspired research into next-generation treatments. Ketamine also has short term dissociative effects, in which individuals report altered consciousness and perceptions of themselves and their environment. However, whether ketamine's dissociative side effects are necessary for its antidepressant effects remains unclear. This perspective examines the relationship between dissociative effects and acute and longer-lasting antidepressant response to ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists. Presently, the literature does not support the conclusion that dissociation is necessary for antidepressant response to ketamine. However, further work is needed to explore the relationship between dissociation and antidepressant response at the molecular, biomarker, and psychological levels.

The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review.

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.

[Treatment of borderline personality disorder with opioid antagonists: buprenorphine, nalmefene, naloxone and naltrexone in the treatment of dissociative symptoms, self-mutilation and suicidal behavior]. / Tratamiento del Trastorno límite de la personalidad con antagonistas opioides: buprenorfina, nalmefeno, naloxona y naltrexona en el tratamiento de síntomas disociativos, automutilaciones y conducta suicida.

OBJECTIVE: Recent theory has proposed that a dysfunction of the opioid system modulates mood, reward and pain; seems to be unstable in people with Borderline Personality Disorder. Our purpose is to analyze the evidence on the efficacy of the use of buprenorphine, nalmefene, naloxone and naltrexone, in the treatment of dissociative symptoms, self-mutilation and suicidal behavior of these patients. METHOD: We conducted a systematic search of MEDLINE and LILACS databases, to retrieve relevant articles. Included studies were experimental and observational designs of borderline personality samples in which dissociative symptoms, self mutilation or suicidal behavior was reported as an outcome and evaluated with some impact measures. RESULTS: A total of eight studies were reviewed. These provided interesting expectations about posible treatment lines in Borderline Personality Disorder using opioid antagonists. The subgroup most benefited was the one who has analgesia and highest number of diagnostic criteria. CONCLUSIONS: Studies of higher methodological quality are needed, in larger population samples and using control of confounding variables that allow us to estimate a value power calculation, and thus be able to support firm conclusions.

Pharmacotherapy for dissociative disorders: A systematic review.

BACKGROUND: Dissociative Disorder (DD) is a large group of disorders that shares common psychopathology. Psychopharmacological agents have sparse evidence in the treatment of DD in general. Multiple pharmacotherapy options have been used without conclusive evidence. METHODS: We conducted a systematic review of data in English language from 1967 to 2019 the protocol of which was registered under PROSPERO (Study ID CRD42019127235). Using PRISMA guidelines, 5 RCTs reporting data on 214 participants providing data on response to pharmacotherapy in dissociative disorder were included. RESULTS: The treatment response rate of pharmacotherapy group as measured in reduction in dissociative symptoms was 68.42% (n = 65/95), significantly higher than that of 39.49% (n = 47/119) in the control group. And, the pooled RR was 1.59 (95% CI, 0.76-3.30; P = 0.21). The overall effect estimates are favourable to pharmacotherapy group over placebo. CONCLUSION: It would be apt to conclude that Paroxetine and Naloxone are the only pharmacological agents studied through RCTs and found to have modest evidence for controlling depersonalization symptoms and dissociative symptoms that are comorbid with PTSD and BPD. Results of this meta-analysis should be interpreted with caution in view of high heterogeneity and scanty literature on RCTs on various subtypes of DD.

The physiological orienting response in female adolescents with borderline personality disorder.

BACKGROUND: The reflexive startle- and orienting-response have been widely studied in psychiatric disorders. Existing evidence in patients with borderline personality disorder (BPD) is mixed, and limited to adults. The present study addressed clinical correlates of the psychophysiological orienting response in adolescents with BPD. METHODS: Female adolescents (13-19 years) with BPD (n = 30), healthy controls (HC; n = 34), and psychiatric clinical controls (CC; n = 53) participated in the trial. Orienting response was induced using acoustic startle-probes (sinus tones) while heart rate (HR) and skin conductance (SCR) were continuously recorded. Besides clinical interviews, the assessment included self-reports on depressive symptoms, anxiety, dissociation and psychopathological distress. RESULTS: On a group level, relative habituation of the HR-response (regression slope) significantly differed between groups (F(2,114) = 3.74, p = 0.027), with significant contrasts (p = 0.026, Sidak corrected) comparing CC (slope 0.04 ±â€¯0.41) and BPD (slope 0.28 ±â€¯0.40). On a dimensional level, relative HR habituation was significantly correlated with the number of BPD diagnostic criteria endorsed (r(117) = 0.183, p = 0.049) and symptoms of dissociation (r(116) = 0.193, p = 0.038), indicating that delayed HR habituation across probes was associated with greater BPD symptom severity. Analyses of SCR showed no significant findings. CONCLUSION: Findings provide preliminary support for altered habituation of the HR orienting response in adolescent BPD, associated with BPD severity - in particular dissociative experiences. Dissociative experiences may alter the automatic defensive response early in the course of BPD, providing a potential pathway to exaggerated emotional responding in BPD.

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression.

BACKGROUND: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. METHODS: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response. RESULTS: Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. LIMITATIONS: Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses. CONCLUSIONS: From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

Response to eperisone in patients of therapy-resistant dissociative convulsions: A report of two cases.

Dissociative convulsions or pseudoseizures are a difficult to treat common psychiatric condition. In a subset of these patients, the chief complaint is clenching of teeth with apparent nonresponsiveness alone. Neither drugs nor psychotherapeutic interventions have been found to be of much help in its management. Report of two such subsets of cases is presented, in which patients with dissociative convulsions showed sudden, dramatic, and sustained good response to the addition of a muscle relaxant eperisone.

Case report: Improvement in dissociative symptoms with mixed amphetamine salts.

Symptoms of dissociation, including dissociative amnesia, depersonalization, and derealization, commonly develop in individuals subject to chronic and repeated trauma during development. This includes the trauma of environmental inability to facilitate development of adequate cognitive strategies for coping with strong negative emotions. Dissociation likely involves dysregulated balance of prefrontal inhibition of limbic structures and inadequate regulation of attentional bias by both prefrontal and limbic systems. There is currently no established psychopharmacologic treatment for dissociative symptoms. Here the case of a woman with severe dissociative symptoms that were markedly improved with the administration of mixed amphetamine salts is discussed. Potential neurobiologic mechanisms for dissociative symptom improvement with psychostimulants are discussed.

Complex Trauma in Adolescents and Adults: Effects and Treatment.

Complex trauma involves multiple exposures to adverse events over the lifespan. Such experiences are associated with a variety of psychological outcomes, including a decreased threshold for the development of posttraumatic stress disorder as well as self-capacity problems and dysfunctional behaviors. Psychological interventions that increase affect regulation, support titrated processing of memories and cognitions, and emphasize the therapeutic relationship seem to be most helpful for complex trauma effects. Pharmacologic treatments have some efficacy in the treatment of the posttraumatic stress components of complex posttraumatic outcomes but are generally less successful in reducing self-related problems and symptoms.

Psychopharmacologic treatment of dissociative fugue and PTSD in an Ethiopian refugee.

Despite widespread awareness of their frequent co-occurrence, little is known about treatment of individuals with comorbid posttraumatic stress disorder (PTSD) and dissociative disorders. Patients with dissociative disorders do not respond well to standard exposure therapy, and few psychopharmacologic trials exist. Fluoxetine proved ineffective for depersonalization disorder, but paroxetine showed efficacy in decreasing dissociative symptoms in PTSD patients.