OPEN Foundation

Author name: OPEN Foundation

Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?

Abstract

BACKGROUND:
Ketamine, administered in subanesthetic doses, is an effective off-label treatment for severe and even treatment-refractory depression; however, despite dozens of studies across nearly 2 decades of research, there is no definitive guidance on matters related to core practice issues.
METHODS:
This article presents a qualitative review and summary about what is known about ketamine dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions.
RESULTS:
Ketamine is most commonly administered in the dose of 0.5 mg/kg, but some patients may respond to doses as low as 0.1 mg/kg, and others may require up to 0.75 mg/kg. The ketamine dose is conventionally administered across 40 minutes; however, safety and efficacy have been demonstrated in sessions ranging between 2 and 100 minutes in duration. Bolus administration is safe and effective when the drug is administered intramuscularly or subcutaneously. Whereas the intravenous route is the most commonly employed, safety and efficacy have been described with other routes of administration, as well; these include oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous routes. Patients may receive a single session of treatment or a course of treatment during the acute phase, and treatment may rarely be continued for weeks to years to extend and maintain treatment gains in refractory cases. When so extended, the ideal frequency is perhaps best individualized wherein ketamine is dosed a little before the effect of the previous session is expected to wear off.
CONCLUSIONS:
There is likely to be a complex interaction between ketamine dose, session duration, route of administration, frequency of administration, and related practice. Until definitive studies comparing different doses, rates of administration, routes of administration, and other considerations are conducted, firm recommendations are not possible. From the point of view of clinical practicability, subcutaneous, intranasal, and oral ketamine warrant further study. If domiciliary treatment is considered, the risk of abuse must be kept in mind.
Andrade, C. (2017). Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?. The Journal of clinical psychiatry78(7), e852-e857. 10.4088/JCP.17f11738
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Ayahuasca: what mental health professionals need to know

Abstract

Background

Ayahuasca is a psychoactive ethnobotanical concoction that has been used for decades by indigenous groups of the Northwestern Amazon and by syncretic religious organizations for ritual and therapeutic purposes. In the last two decades, it is being used worldwide in evolving practices. Ayahuasca seem to therapeutic effects, but controlled studies are lacking. Moreover, its safety and toxicity are not completely understood.

Objectives

To present an overview of the effects of ayahuasca based on the most recent human studies.

Methods

Narrative review.

Results

Ayahuasca administration in controlled settings appears to be safe from a subjective and physiological perspective, with few adverse reactions being reported. More frequent adverse reactions occur in non-controlled settings. Prolonged psychotic reactions are rare and seem to occur especially in susceptible individuals. Ayahuasca showed antidepressive, anxiolytic, and antiaddictive effects in animal models, observational studies, and in open-label and controlled studies.

Discussion

Ayahuasca administration in controlled settings appear to be safe. Moreover, ayahuasca seem to have therapeutic effects for treatment-resistant psychiatric disorders that should be further investigated in randomized controlled clinical trials. However, medical complications and cases of prolonged psychotic reactions have been reported, and people with personal or family history of psychotic disorders should avoid ayahuasca intake.

Santos, R. G. D., Bouso, J. C., & Hallak, J. E. C. (2017). Ayahuasca: what mental health professionals need to know. Archives of Clinical Psychiatry (São Paulo)44(4), 103-109. 10.1590/0101-60830000000130
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LSD experiments by the United States Army

Abstract

Extensive LSD testing was conducted by the US Army at Edgewood Arsenal and other locations from 1955 to 1967. A number of different reports have been produced describing the health effects of this testing, including the Veterans Health Initiative Report in 2003. By and large, these reports gloss over and minimize the short and long-term side effects and complications of this testing. However, the reports themselves document frequent, severe complications of the LSD. These side effects were regarded by the Army as having been directly caused by the LSD exposure. In view of the current resurgence of interest in hallucinogens within psychiatry, the sanitized version of the effects of LSD exposure on US soldiers needs to be replaced with a more accurate account.
Ross, C. A. (2017). LSD experiments by the United States Army. History of Psychiatry, 0957154X17717678.
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Self unbound: ego dissolution in psychedelic experience

Abstract

Users of psychedelic drugs often report that their sense of being a self or ‘I’ distinct from the rest of the world has diminished or altogether dissolved. Neuroscientific study of such ‘ego dissolution’ experiences offers a window onto the nature of self-awareness. We argue that ego dissolution is best explained by an account that explains self-awareness as resulting from the integrated functioning of hierarchical predictive models which posit the existence of a stable and unchanging entity to which representations are bound. Combining recent work on the ‘integrative self’ and the phenomenon of self-binding with predictive processing principles yields an explanation of ego dissolution according to which self-representation is a useful Cartesian fiction: an ultimately false representation of a simple and enduring substance to which attributes are bound which serves to integrate and unify cognitive processing across levels and domains. The self-model is not a mere narrative posit, as some have suggested; it has a more robust and ubiquitous cognitive function than that. But this does not mean, as others have claimed, that the self-model has the right attributes to qualify as a self. It performs some of the right kinds of functions, but it is not the right kind of entity. Ego dissolution experiences reveal that the self-model plays an important binding function in cognitive processing, but the self does not exist.
Letheby, C., & Gerrans, P. (2017). Self unbound: ego dissolution in psychedelic experience. Neuroscience of Consciousness3(1). 10.1093/nc/nix016
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Self unbound: ego dissolution in psychedelic experience.

Abstract

Users of psychedelic drugs often report that their sense of being a self or ‘I’ distinct from the rest of the world has diminished or altogether dissolved. Neuroscientific study of such ‘ego dissolution’ experiences offers a window onto the nature of self-awareness. We argue that ego dissolution is best explained by an account that explains self-awareness as resulting from the integrated functioning of hierarchical predictive models which posit the existence of a stable and unchanging entity to which representations are bound. Combining recent work on the ‘integrative self’ and the phenomenon of self-binding with predictive processing principles yields an explanation of ego dissolution according to which self-representation is a useful Cartesian fiction: an ultimately false representation of a simple and enduring substance to which attributes are bound which serves to integrate and unify cognitive processing across levels and domains. The self-model is not a mere narrative posit, as some have suggested; it has a more robust and ubiquitous cognitive function than that. But this does not mean, as others have claimed, that the self-model has the right attributes to qualify as a self. It performs some of the right kinds of functions, but it is not the right kind of entity. Ego dissolution experiences reveal that the self-model plays an important binding function in cognitive processing, but the self does not exist.
Letheby, C., & Gerrans, P. (2017). Self unbound: ego dissolution in psychedelic experience. Neuroscience of consciousness2017(1), nix016., 10.1093/nc/nix016
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A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

Abstract

Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.
Dolder, P. C., Grünblatt, E., Müller, F., Borgwardt, S. J., & Liechti, M. E. (2017). A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects. Frontiers in Pharmacology8. 10.3389/fphar.2017.00423
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Isolated non-cardiogenic pulmonary edema – A rare complication of MDMA toxicity

Abstract

This is a case of a 19-year-old male who presented to the medical tent at an outdoor electronic dance music festival (EDMF) due to an altered mental state in the setting of acute 3,4-methylenedioxymethamphetamine (MDMA) intoxication. He was noted to be in severe respiratory distress, required endotracheal intubation in the field and subsequently developed Acute Respiratory Distress Syndrome (ARDS) without other acute organ dysfunction. He was hospitalized for 5days requiring endotracheal intubation and mechanical ventilation. By presenting this case, we will explore and discuss the cardiopulmonary effects of MDMA intoxication that can lead to a rare, deleterious complication of MDMA intoxication other than previously reported adverse outcomes.
Haaland, A., Warman, E., Pushkar, I., Likourezos, A., & Friedman, M. S. (2017). Isolated non-cardiogenic pulmonary edema—A rare complication of MDMA toxicity. The American journal of emergency medicine35(9), 1385-e3. 10.1016/j.ajem.2017.06.040
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Ketamine for Depression, 3: Does Chirality Matter?

Abstract

Ketamine is a racemic mixture of the enantiomers R-ketamine and S-ketamine (esketamine). S-ketamine has greater analgesic and anesthetic effects than R-ketamine and is less likely to cause psychotomimetic and other adverse effects. There is therefore an emerging interest favoring the use of S-ketamine over racemic ketamine when the drug is used for analgesia or anesthesia. This article examines preclinical and clinical literature on the antidepressant properties of S-ketamine. Animal data suggest potential advantages for R-ketamine over S-ketamine. Case reports, case series, and some small randomized controlled trials suggest that single or repeated intravenous infusions (0.2-0.4 mg/kg) or intranasal administrations (28-84 mg) of S-ketamine have antidepressant action in patients with medication-refractory depression and that the observed benefits are similar in magnitude to the antidepressant benefits reported with racemic ketamine. However, there are no direct comparisons between S-ketamine and either R-ketamine or racemic ketamine in depressed patients; therefore, it is not possible to make an informed choice when considering the enantiomers and the racemate for the indication of depression.
Andrade, C. (2017). Ketamine for Depression, 3: Does Chirality Matter?. The Journal of clinical psychiatry78(6), e674-e677. 0.4088/JCP.17f11681
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Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review

Abstract

BACKGROUND:
This study evaluated efficacy and safety of intravenous subanesthetic doses of esketamine using an administration time of 10 minutes in patients with treatment-resistant depression and bipolar depression.
METHODS:
A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant depression and bipolar depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and these patients received rapid infusion of esketamine between June 2012 and December 2015. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered to measure and score depressive symptom severity before infusion and at 24 hours, 72 hours, and 7 days after infusion. In addition, Clinical Global Impression scale was administered before and 7 days after esketamine infusion.
RESULTS:
Esketamine was administered to 30 patients. A total of 27 patients met the inclusion criteria and had MADRS evaluation data, which showed that 23 had unipolar and 4 had bipolar depression. Thirteen patients (48.1%) showed therapeutic response (MADRS reduction ≥50%) within 1 week (7 days) of intervention. Remission (MADRS <7) was observed in 10 patients (37.0%) in the same period. Therapeutic response and remission frequencies were seen in 16 (59.3%) and 11 (40.7%) patients, respectively, within 24 hours following drug infusion. The most relevant side effect observed during the esketamine infusion was dissociative symptoms ranging from mild to severe, which was reported by 11.1% of patients as a very disturbing experience.
LIMITATIONS:
This study was done retrospectively, had a small sample size, and there was no comparative group.
CONCLUSION:
The present study demonstrates that rapid infusion of esketamine is possibly not the optimal choice to administer this drug for treatment-resistant depression due to tolerability reasons. Further controlled studies are required to investigate efficacy, safety, and tolerability profiles among the different types of ketamines and methods of using this drug in depressed patients.
Correia-Melo, F. S., Argolo, F. C., Araújo-de-Freitas, L., Leal, G. C., Kapczinski, F., Lacerda, A. L., & Quarantini, L. C. (2017). rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review. Neuropsychiatric disease and treatment13, 1627. 10.2147/NDT.S135623
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Journal Club #22: Applying the EU Regulatory Framework to Determine the Benefit–Risk Profile of Psychedelics - March 3