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Chiara Rolle, Mario Scheib, Anja Frank, Isabella Russ

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Abstract

The most reported symptom of post-COVID syndrome is pronounced fatigue.In this case series, we present the treatment of four patients suffering from Post-COVID syndrome after more than 3 months since infection, presented diagnostically within the framework of chronic fatigue syndrome (CFS). They were treated with a combination of Low-frequency (1 Hz) repetitive transcranial magnetic stimulation(rTMS) and ketamine intravenous (IV) infusion therapy for a period of 2 to 3 weeks. Three patients experienced significant improvement. Given the promising results further research is indicated.

Keywords:

Post-COVID Syndrome; SARS-CoV-2; Ketamine; rTMS; Chronic Fatigue Syndrome; Neuroplasticit

Citation:

Chiara Rolle, Mario Scheib, Anja Frank, Isabella Russ. Treatment of Chronic Fatigue Syndrome (CFS) in Post-SARS-CoV-2 Infection through combined outpatient Neuromodulation Therapy with Repetitive Transcranial Magnetic Stimulation (rTMS) and Ketamine IV Therapy – A Case Series.Int Clinc Med Case Rep Jour. 2023;2(6):1-7.

Akinosoglou K, Gogos A, Papageorgiou C, Angelopoulos E, Gogos C. Ketamine in COVID-19 patients: Thinking out of the box. J Med Virol. 2021 Jul;93(7):4069-4070. doi: 10.1002/jmv.26681. Epub 2020 Dec 1. PMID: 33215721; PMCID: PMC7753268.

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Background. There are few studies on ketamine and its properties to work with addiction (alcohol, opioid, cannabis, and cocaine use disorder). The studies show that ketamine treatment can help reduce craving and support abstinence [14]. Hypnotherapy is an evidence-based treatment gaining popularity for treating addiction, but not everybody can be hypnotized due to different levels of suggestibility. Our clinical practice has observed that people who are not highly hypnotizable, such as patients with obsessive-compulsive disorders, become more suggestible accompanied by our newly developed method called “Ketamine-Hypnosis package” (KHP). In this case report and study, we want to explore and evaluate the potential of KHP in working with addiction. Diagnostic and a qualitative content analysis should give profound insights into the treatment process and method.

Case Report. The subject is a 48-year-old male German Social Worker with treatment-resistant depression, suicidal thoughts, obsessive behavior, and several forms of addiction. The patient received a 10-day treatment at Instituto Dr. Scheib, with Diagnostic, rTMS, neurofeedback, and four sessions of KHP. Every Ketamine infusion remained with a standard dose of 0.5 mg/kg R-Ketamine for about 45 minutes.

Results. Primary outcome measures included change in depression as measured by the BDI-II with a reduction from 44, highly depressed, to a score of 3, no depression, and change of symptoms measured by the SCL-90 R that showed a clear reduction in almost every factor vs. baseline. The qualitative content analysis of the KHP sessions identified nine categories; Setting, Intervention, Body, Control, Feelings, Insights/Realizations, Addiction, Depression and Imagery. QEEG measurements before and after treatment showed a pattern of over-representation of slow brain activity with closed eyes, which can be observed in fluctuating concentration and volatile impulse control. Follow-Up Data with BDI-II one week after treatment showed factor 3 and 5 weeks after treatment factor 15.

Conclusions. The 10-day-treatment program improved numerous important treatment outcomes in one substance-dependent adult engaged in hypnotherapeutic modification, including promoting less substance abuse, diminishing craving, and reducing the risk of relapse. Further research is needed to replicate these promising results in a larger sample.

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Journal of Psychiatric Research

Available online 11 December 2020

Authors: Jiaqi Xiong¹ Orly Lipsitz³ David Chen-Li³ Joshua  D.Rosenblat¹²³ Nelson  B.Rodrigues³ Isabelle Carvalho³ Leanna M.W. Lui³ Hartej Gill³⁴ Flora Narsi³ Rodrigo B. Mansur³ Yena Lee³ Roger S. McIntyre¹²³⁴

https://doi.org/10.1016/j.jpsychires.2020.12.038Get rights and content

Highlights

• Single-dose intravenous ketamine/intranasal esketamine has rapid and robust acute effects in reducing suicidal ideation (SI).

• Future high-quality research on the anti-SI efficacy of alternative administration routes (i.e. intramuscular, subcutaneous, oral/sublingual) and formulations of ketamine is needed.

• Dosage, routes of administration, and formulations are factors to be considered for optimizing SI treatment using ketamine.

Abstract

The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase, Medline, and PubMed from inception to July 1^st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n=197), the pooled effect size for anti-SI effects at 24-hour time point was 1.035 (N=6, CI: 0.793 to 1.277, p<0.001) for intravenous (IV) racemic ketamine and 1.309 (N=1, CI: 0.857 to 1.761, p<0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/IN esketamine is associated with robust reductions in suicidal thoughts at 2-hour, 4-hour, and 24-hour post-intervention. In addition, future studies on IM/oral/sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 105, 8 March 2021, 110126

Authors: Orly Lipsitz^ab Roger  S.McIntyre^abcd Nelson  B.Rodrigues^ab Tyler S. Kaster^dh Danielle  S. Cha^ab Elisa Brietzke^jk Hartej Gill^ab Flora Nasri^a Kangguang Lin^ef Mehala Subramaniapillai^ab Kevin Kratiuk^b Kayla Teopiz^b Leanna M.W. Lui^a Yena Lee^ab Roger Ho^g Margarita Shekotikhina^abi Rodrigo B. Mansur^ad Joshua  D. Rosenblat^abcd

https://doi.org/10.1016/j.pnpbp.2020.110126Get rights and content

Highlights

• Early symptom improvement was associated with greater antidepressant effects following four ketamine infusions.

• ~40% of individuals with early improvement responded to the full treatment course versus 14–19% in non-early improvers.

• 58% of individuals who did not experience early improvement experienced a partial to full response after the fourth infusion.

Abstract

Background

Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions.

Method

134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report₁₆ (QIDS-SR₁₆) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR₁₆ scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR₁₆ scores after controlling for baseline characteristics.

Results

Early improvement post-infusion 1 (β = −3.52, 95% BCa CI [−5.40, −1.78]) and 2 (β = −3.16, 95% BCa CI [−5.75, −1.59]) both significantly predicted QIDS-SR₁₆scores post-infusion 4. Early improvers had significantly lower QIDS-SR₁₆ scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR₁₆) post-infusion 4.

Limitations

This is a post-hoc analysis of an open-label study.

Conclusion

Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited.

Steven R.D. Best a,*, Dan G. Pavel b, Natalie Haustrup c

a The Neuroscience Center, Deerfield, IL, USA
b PathFinder, Brain SPECT Imaging, Deerfield, IL, USA
c Haustrup Scientific Consulting, Cambridge, UK

A R T I C L E  I N F O

Keywords: Psychiatry, Neurology, TMS, Depression, Ketamine, Comorbidity, Biomarker, Combination

A B S T R A C T

Background: Both transcranial magnetic stimulation (TMS) and infused ketamine are recognized treatments for patients suffering from major depressive disorder (MDD). A novel therapy named combination TMS with ketamine (CTK) is introduced. This retrospective review examined the safety and clinical benefits of CTK in patients suffering from treatment-resistant depression (TRD) during the routine practice of psychiatry in a private clinic.

Methods: TRD patients (N . 28) received a coincident application of high-output TMS (30 minutes) with biomarker-determined ketamine infusions (20 minutes). Frequency of treatment was dependent on patient responsiveness (10–30 sessions). Clinical global impression (CGI) data was collected pre- and post-treatment and then two years later.

Results: The mean reduction in CGI severity for the patient group following CTK was 4.46 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (α . 0.01, t . 22.81 p < 0.0001).
This reduction was sustained for two years following treatment completion and this remission was deemed statistically significant by a second paired t-test (α . 0.01, t . 27.36, p < 0.0001).

Limitations: Retrospective review of a limited number of patients undergoing CTK in a clinical practice.

Conclusions: This clinical review indicated that CTK is an effective, long-term therapy (after two years) and can be used for TRD patients. The coincident administration of ketamine allowed for higher TMS intensities than otherwise would be tolerated by patients. Further studies for optimization of CTK are warranted.

1. Introduction

Treatment-resistant depression refers to a major depressive disorder (MDD) with a lack of clinically meaningful improvement to an appropriate course (adequate dose over 6–8 weeks) of at least two antidepressants from different pharmacological classes, prescribed for adequate duration, with adequate affirmation of treatment adherence (Little, 2009; EMA Guidelines, 2013). It is estimated that between 15% and 33% of patients will not respond to multiple interventions and therefore be classed as suffering from treatment-resistant depression (Little, 2009).

The sequenced treatment alternatives to relieve depression (STAR*D) trial explored the effectiveness of alternative treatments for treatment-resistant depression patients and predicted that only a third of the 20 million Americans suffering from MDD would achieve remission (Warden et al., 2007). Continued depressive symptoms have been linked to social issues, a greater risk of suicide and mortality and ultimately results in increased health-care costs (Lepine and Briley, 2011; Kellar et al., 2016).

The cause of such depressive disorders remains unclear. However, it is commonly agreed that it relates to a system disorder affecting pathways between cortical, subcortical and limbic sites, along with the neurotransmitter and molecular mediators (Mayberg et al., 2005). Patients with unipolar depression have been shown to have prefrontal abnormalities, predominantly on the left and decreased neuronal activities in the dorsolateral prefrontal cortex (PFC) regions, as well as in the rostral anterior cingulate cortex (ACC) areas, closely connected to the dorsolateral PFC (Baeken and De Raedt, 2011).

Research has shown a strong negative correlation between the ACC

* Corresponding author.

E-mail address: srdbest@neuroscience.md (S.R.D. Best).

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Heliyon

journal homepage: www.heliyon.com

https://doi.org/10.1016/j.heliyon.2019.e02187

Received 28 February 2019; Received in revised form 31 May 2019; Accepted 26 July 2019

2405-8440/© 2019 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published: 29 August 2017

• Jerome H Taylor,
• Angeli Landeros-Weisenberger,
• Catherine Coughlin,
• Jilian Mulqueen,
• Jessica A Johnson,
• Daniel Gabriel,
• Margot O Reed,
• Ewgeni Jakubovski&
• Michael H Bloch

Neuropsychopharmacology  volume 43, pages325–333(2018) Cite this article

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Abstract

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F_9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F_10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

Paul Glue, Shona Neehoff, Amandine Sabadel, …

First Published September 17, 2019 Research Article Find in PubMed

https://doi.org/10.1177/0269881119874457

Article information 

Abstract

Background:

We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders.

Aims:

The purpose of this study was to replicate our earlier report about ketamine‘s anxiolytic activity, using a more robust study design.

Methods:

This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations.

Results:

Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments.

Conclusions:

Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

Jennifer L. Phillips1,2, Sandhaya Norris1,2, Jeanne Talbot1,2, Taylor Hatchard1, Abigail Ortiz 1, Meagan Birmingham1, Olabisi Owoeye1,2, Lisa A. Batten1 and Pierre Blier1,2,3

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen’s d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

Neuropsychopharmacology (2019) 0:1–7; https://doi.org/10.1038/s41386-019-0570-x

Muris Humo^a, Beyza Ayazgök^ab, Léa J.Becker^a, Elisabeth Waltisperger^a, Tomi Rantamäki^cd, Ipek Yalcin^a

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 100, 8 June 2020,

https://doi.org/10.1016/j.pnpbp.2020.109898

Abstract

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until up to 72 h. Altogether, these findings provide insight into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.

Aust N Z J Psychiatry. 2020 Jan;54(1):29-45. doi: 10.1177/0004867419883341. Epub 2019 Nov 15.

Witt K¹, Potts J^2,3, Hubers A^1,4, Grunebaum MF⁵, Murrough JW⁶, Loo C⁷, Cipriani A^2,3, Hawton K^1,2.

Author information

Abstract

OBJECTIVE: 

Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality.

METHOD: 

CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes.

RESULTS: 

Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = -0.51, 95% confidence interval = [-1.00, -0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = -0.63, 95% confidence interval = [-0.99, -0.26]; between 24 and 72 hours: standardised mean difference = -0.57, 95% confidence interval = [-0.99, -0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine.

CONCLUSION: 

A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.

Abstract

Steven Richard Devore Best & Brian Griffin

Pages 232-234 | Received 19 Aug 2013, Accepted 09 Jun 2014, Accepted author version posted online: 13 Jun 2014, Published online: 23 Jul 2014

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• https://doi.org/10.3109/00207454.2014.933834

In the present article, we report on the case of a 23-year-old woman with a history of treatment-resistant depression who achieved significant symptom improvement with a novel treatment consisting of ketamine, a dissociative anesthetic, and external neuromodulation with transcranial magnetic stimulation (TMS). This case highlights the need for further investigation of treatments pairing external neuromodulation with dissociative anesthetics.

Despite advances in pharmacological treatment, approximately half of patients fail to achieve full remission, prompting researchers to look beyond conventional antidepressant medications [1]. Recent research has examined transcranial magnetic stimulation (TMS and its variant rTMS), in which an electromagnetic stimulator positioned at the scalp induces a change in local and distant electric field conditions and may cause an associated depolarization of neurons [2]. When used to stimulate the dorsolateral prefrontal cortex, rTMS has been associated with significant antidepressant effects [3], and is an FDA-approved treatment for depression. However, it is difficult to achieve remission with rTMS alone. A separate body of research has investigated intravenous ketamine, an N-methyl-D-aspartate (NMDA) antagonist [4–8]. In contrast to typical antidepressant medications that take effect within several weeks, ketamine provides relief within 2 h and lasts between four and seven days, after which relapse is common [4,5]. To date, little is known about the possible synergistic effects of combined rTMS/ketamine treatment for depression.

One study found that a factor underlying treatment resistance in depression is abnormal function in a thalamocortical circuit involving the anterior cingulate cortex (ACC), among other areas [9,11]. Accordingly, the first author hypothesized stimulating the ACC with TMS would restore normal functioning in the relevant circuit, thereby improving response to ketamine. We report on a depressed patient treated with a novel combined ketamine/TMS technique who showed substantial improvement in depression symptomatology at the end of treatment, and again at follow-up 483 days later. An IRB exemption was obtained from an independent accredited agency.

Case Report. Patient X is a 23-year-old woman who presented with a 9-year history of depression that did not respond to treatment with sertraline, buprorion, paroxetine, or stimulants. She also presented with attention deficit disorder that was treated with amphetamine from intake through follow-up. Her past history included diagnoses of anorexia nervosa and substance abuse (cocaine) that were in full remission at intake. Patient X was systematically assessed for psychopathology by an independent licensed psychologist at the outset of treatment. The primary assessment instruments were the Beck Depression Inventory-II (BDI-II) and the Personality Assessment Inventory (PAI). PAI subscale scores greater than 70 indicate clinically significant difficulties. Results of this assessment suggested that Patient X exhibited moderate levels of depression (BDI-II = 17, PAI DEP T = 84) consisting predominantly of depressed mood (PAI DEP-A T = 83), low self-esteem (PAI DEP-C T = 87), and suicidal ideation (PAI SUI T = 62). In addition, the initial assessment suggested significant difficulties in developing and maintaining a sense of life purpose and self-identity (PAI BOR-I T = 80), problematic alcohol use (PAI ALC = 66), and concentration difficulties (PAI SCZ-T T = 73). After this comprehensive assessment, Patient X’s mood was assessed during each treatment by the first author using a visual analog scale. In this measure, Patient X indicated where her mood fell along a continuum from “the worst I can imagine feeling” to “the best I can imagine feeling.”

Prior to beginning combined treatment, Patient X was given 2 days of rTMS pretreatment (four treatments per day of 30 min with 45 min of rest between treatments). Combined ketamine/TMS treatment began the following day and continued at weekly intervals for 13 weeks. Fifteen years of observational evidence from our clinic suggested that this duration produced clinically significant results. Combined treatment consisted of 40 min of 1 Hz continuous TMS with an intravenous ketamine infusion administered concurrent to and bracketed within the middle 30 min of TMS, resulting in 5 min of TMS pre- and postinfusion. The dosage of infused ketamine increased gradually from 30 mg at the first treatment to 100 mg at the last treatment. During combined treatment, the TMS head coil (manufactured by Neotonus) was positioned at the midline of the scalp to achieve maximal stimulation of the medial prefrontal area that overlays the anterior cingulate, a region implicated in depression [10]. While direct stimulation of the anterior cingulate is not likely given its subcortical position and the limited electromagnetic field penetration of TMS coils [4], we hypothesized that indirect stimulation of the anterior cingulate via TMS applied to the overlaying scalp region would result in a beneficial effect.

Baseline brain scans were used to ensure accurate coil positioning at each treatment. TMS treatments were administered at 115% of motor threshold at 1 Hz continuous pulsation given that these settings were within safety guidelines and consistent with previous research. Using this method, we hypothesized that the dissociative effects of ketamine along with TMS activation of the anterior cingulate would help reestablish normal oscillatory rhythms in this region, leading to a decrease in depression symptoms.

After the treatment on week three, Patient X reported a substantial improvement in mood and energy levels. Patient X noted that these gains were maintained over the duration of treatment with some fluctuation in mood due to relationship difficulties. Soon after the last combined treatment, Patient X reported a nondepressed mood with increased motivation and diminished attention difficulties. Combined treatment was followed by regular psychiatric visits 1–2× /month for 14 months. Gains were generally maintained over this span, with Patient X reporting that she was able to begin graduate studies and sustain an intimate relationship. Four hundred and eighty three days after her initial assessment, Patient X was again systematically assessed for psychopathology by an independent licensed psychologist. Results showed substantial decreases in depression (BDI-II = 0, PAI DEP T = 41), suicidal ideation (PAI SUI T = 45), alcohol use (PAI ALC T = 49), and concentration difficulties (PAI SCZ T = 49), along with increased sense of self-purpose (PAI BOR-I T = 56).

Discussion. This case report adds to the literature on improving the efficacy of brain electromagnetic stimulation by administering pharmacological agents that modulate glutamatergic transmission. Whereas previous research suggests that rTMS is somewhat effective in treating depression [3], and that subanesthetic doses of ketamine are temporarily helpful with depression [5–9]; the present case report is the first to suggest that a combined ketamine/rTMS treatment may be a more efficacious treatment for refractory depression than either infused ketamine or rTMS alone. Future research should examine combined ketamine/TMS treatment in a randomized controlled trial.

Declaration of Interest

Dr. Best reports no biomedical financial interests or potential conflicts of interest. Brian Griffin reports no biomedical financial interests or potential conflicts of interest. The authors alone are responsible for the content and writing of this paper.

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The fast-acting nasal spray esketamine, marketed as Spravato^TM, was recently approved by the Food and Drug Administration (FDA) to treat depression in individuals whose depression has been resistant to at least two medications. Structurally, esketamine is an enantiomer, or mirror image, of ketamine and works by a similar mechanism.¹ The antidepressant response is evident within a few days of administration, unlike traditional antidepressants that often take weeks for the patient to feel any improvement in mood. This is particularly advantageous for patients who have suicidal thoughts and need quick resolution of depression symptoms.

While an old anesthetic drug, this new formulation has yet to be explored extensively through clinical studies in the pregnant and breastfeeding population. Interestingly, animal studies conducted don’t seem to produce promising results. A new study conducted in 2017 found that offspring of pregnant rats treated with ketamine had impaired learning and memory.² Another study found that offspring of rats treated with ketamine during the second trimester had long-term neurocognitive dysfunction.³ A study in 2016 found that ketamine exposure during pregnancy in rats resulted in reduced development of certain brain regions in the offspring.⁴ Thus, at this time, ketamine’s effects in pregnancy are concerning and it is not recommended for use during pregnancy. Although the FDA has not assigned a pregnancy category to esketamine, the pharmaceutical provider suggests that Spravato^TM may cause fetal toxicity and should be avoided in pregnant and breastfeeding women.⁵

This is not to say that women shouldn’t seek treatment for depression during pregnancy, however. It is instead recommended that pregnant or potentially soon-to-be pregnant women turn to older antidepressants, such as select serotonin reuptake inhibitors (SSRIs). The more popular antidepressants used during pregnancy include sertraline, escitalopram, or fluoxetine.⁶ Paroxetine has been associated with an increased risk of cardiac defects in exposed infants with exposure in the 1^st trimester.⁶ Bupropion is another alternative treatment for depression in pregnant mothers. Treatment should be initiated on a case-by-case basis depending on severity of symptoms and personal history. All of these aspects should be discussed with a physician before initiating therapy. Medication changes should ideally be made prior to pregnancy.⁶

Common antidepressants in pregnancy:

Conclusions

• Esketamine has not been studied extensively in pregnant women, but has shown negative effects on exposed offspring in rats.
• Esketamine is not currently recommended for pregnant women.
• Other antidepressants, such as an SSRI or bupropion, should be considered for depression in pregnancy.
• Medication changes should ideally be made before pregnancy and should be initiated on case-by-case basis with individualized treatment.
• An appropriate dose for an adult is 56 mg (2 sprays total intranasally) administered on day 1 of treatment, then 56-84 mg (2-3 sprays total) twice weekly for 4 weeks.⁵
• It is important to remember that untreated depression during pregnancy is very risky and mothers should seek treatment for depression during pregnancy.

Erika Anderson MS4

Thomas W. Hale, Ph.D.

Teresa Baker MD

Infantrisk Center

Resources:

1. Paddock, Catharine. “The FDA Approve Esketamine Nasal Spray for Severe Depression.” Medical News Today, MediLexicon International, 8 Mar. 2019, www.medicalnewstoday.com/articles/324656.php.
2. Li, Xinran, et al. “Ketamine Administered Pregnant Rats Impair Learning and Memory in Offspring via the CREB Pathway.” Oncotarget, vol. 8, no. 20, 2017, doi:10.18632/oncotarget.15405.
3. Li, Yanan, et al. “Long-Term Neurocognitive Dysfunction in Offspring via NGF/ ERK/CREB Signaling Pathway Caused by Ketamine Exposure during the Second Trimester of Pregnancy in Rats.” Oncotarget, vol. 8, no. 19, 2017, doi:10.18632/oncotarget.16042.
4. Dong, C., et al. “Ketamine Exposure during Embryogenesis Inhibits Cellular Proliferation in Rat Fetal Cortical Neurogenic Regions.” Acta Anaesthesiologica Scandinavica, vol. 60, no. 5, 2016, pp. 579–587., doi:10.1111/aas.12689.
5. “SPRAVATO™ Treatment Center.” Spravato Esketomine, www.spravatotreatmentcenter.com/.
6. Payne, Jennifer L., and Samantha Meltzer-Brody. “Antidepressant Use During Pregnancy: Current Controversies and Treatment Strategies.” Clinical Obstetrics and Gynecology, vol. 52, no. 3, 2009, pp. 469–482., doi:10.1097/grf.0b013e3181b52e20.

Read the clinical study at neurosciencenews.com

Read the study (PDF): Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder

Read the study (PDF): Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder

Read the study here (PDF) : Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression

Adriana Feder M.D., Sara Costi, M.D., Sarah B. Rutter, M.A., Abigail B. Collins, B.S., Usha Govindarajulu, Ph.D., Manish K. Jha, M.D., Sarah R. Horn, M.A., Marin Kautz, M.A., Morgan Corniquel, M.A., Katherine A. Collins, Ph.D., M.S.W., Laura Bevilacqua, M.D., Ph.D., Andrew M. Glasgow, M.D., Jess Brallier, M.D., Robert H. Pietrzak, Ph.D., M.P.H., James W. Murrough, M.D., Ph.D.,Dennis S. Charney, M.D.

Published Online: American Journal of Psychiatry, 5 Jan 2021 https://doi.org/10.1176/appi.ajp.2020.20050596

Abstract

Deborah Brauser, January 18, 2021Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder (PTSD), new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks.

No serious TRAE were reported. Some dissociative symptoms occurred during the ketamine infusion, with the highest levels toward the end of the infusion, but these had resolved by the time of the next assessment 2 hours after infusion.

The most commonly reported adverse event in the ketamine group compared with midazolam after the start of the infusion was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).

“Widespread improvement”
“Overall, the results in this patient population indicate that repeated ketamine infusions over 2 weeks are associated with marked, clinically significant improvement in PTSD symptomatology,” the investigators write, and Feder found them “very satisfactory.”

“It was also encouraging to hear what some of the participants had to say. For example, some reported how their symptoms and feelings had changed over the course of ketamine treatment, with them feeling stronger and better able to cope with their trauma and memories.”

She added, however, that the study was not specifically designed to evaluate ketamine for treatment-resistant PTSD. “Some patients had already had several unsuccessful treatments, while others had never been treated. Efficacy in treatment-resistant PTSD is an important question for future investigation,” Feder said.

Overall, the results in this patient population show that repeated ketamine infusions over 2 weeks are associated with marked, clinically significant improvement in PTSD symptomatology. Dr. Adriana Feder and colleagues
Other areas worth exploring in the future would be the efficacy of the treatment in patients with different forms of trauma and whether the results lasted longer in patients receiving ketamine plus psychotherapy, she noted.

“I don’t want to ignore the fact that the treatments currently available work for a number of people with chronic PTSD. But since there are many more people for whom these treatments do not help or do not help enough, this is certainly a potentially very promising approach to add to a clinician’s treatment repertoire,” Feder said.

Continue reading at Medscape

Link to study:

Comparative efficacy of racemic ketamine and esketamine for depression_ A systematic review and meta

Igor Kungurtsev, M. D.

The recent changes in the former Soviet Union have allowed Russian and American researchers to

communicate freely for the first time since the October Revolution. Prior to these changes, the story of

Russian psychedelic research had remained a mystery in the West. The following article is one of the first

reports of psychedelic research to emerge from Russia as well as the first published outcome study of

ketamine-assisted psychotherapy.

Igor Kungurtsev, M.D. is a research associate at the Bekhterev Psychoneurological Research Institute in

St. Petersburg, Russia, and a psychiatrist in private practice. Kungurtsev is also Vice Chairman of the St.

Petersburg Transpersonal Association, and a member of the Board of Advisors of the Albert Hofmann

Foundation.

About five years ago, our research team obtained permission from the Central Pharmacological

Committee in Moscow to use ketamine as an adjunct to psychotherapy with alcoholics. Ketamine is an

anesthetic used in modern medicine which can also be used in subanesthetic doses to safely and reliably

induce transpersonal states with profound healing potential. This paper will review the phenomenology of

the ketamine state, the procedure for ketamine-assisted psychotherapy, and the preliminary results of our

study with alcoholic and neurotic patients.

Ketamine, 2-(o-chlorophenyl)-2-(methyl-amino) cyclohexanone HCL, has several advantages over other

psychedelics as an adjunct to psychotherapy. It is short acting, the psychoactive effects lasting about an

hour. In addition, ketamine is not scheduled like other psychedelics. In lower doses (about one sixth to

one tenth of that usually used in surgery), it induces profound transpersonal states. My colleagues and I

adopted the transpersonal paradigm as a result of our personal and clinical experience with ketamine

before we had become acquainted with the literature on psychedelics and altered states of consciousness.

At first, we attempted to use ketamine solely as a means of increasing the patient’s suggestibility. The

psychotherapist could then place suggestions of sobriety more deeply into the patient’s subconscious.

Anesthesiologists have reported that ketamine frequently induces states of confusion, feelings of death

and dying, and unpleasant hallucinations. This is known as the “emergence reaction”, and is considered to

be a negative side effect of ketamine in surgical patients who are unprepared for these psychological

effects.

Subsequently, we had the idea that we could associate these feelings of death and dying with the smell and

taste of alcohol (an aversive conditioning model). Not long after we started our research, however, we

came across situations which were incompatible with this paradigm. After ketamine injections, many of

our patients reported very strange experiences. They began to report that they felt disconnected from their

bodies, and that they were “floating” in strange worlds. Some of them, for the first time in their lives,

spoke about God, the meaning of life, and their relationships. Although we tried to help our patients form

negative associations and develop an aversion to alcohol, their experience was more profound and

mystical, sometimes with no relationship to our suggestions or psychotherapy.

At this point, I undertook a series of self-administrations which completely changed my conception of the

ketamine experience. I tried various dosages in order to choose the level most appropriate for our patients.

Three or four minutes after the first injection, I felt this world begin to disappear, and I experienced

myself as a point of consciousness which was floating in strange worlds. The most unusual feeling was

that I had no body, yet somehow “I” existed. The next development was indescribable. During the first

stage, I seemed to exist only as a point of consciousness, but still, “I” existed. Then there was a stage

where even this disembodied sense of self began to disappear, and I felt a real terror of dying. At that

moment I managed to surrender and let go. All that remained was awareness; there was no “I” as me, as

an individual point of consciousness. It was as if there existed only that which was aware of itself.

This experience profoundly changed my view of ketamine, and gave me new insight into some esoteric

concepts of Buddhism and other Eastern philosophies. It profoundly changed my understanding of death

and dying as well.

For several days after this session, I had a feeling of inner surrender, as if my life was a game that I was

playing very easily. While I performed my daily activities, I was very calm and centered inside. It was a

remarkable feeling. After this self-experimentation, we changed our paradigm and adopted a transpersonal

approach. We now refer to this treatment as “Death-Rebirth” Psychotherapy.

The research is done in a comparatively large hospital for the treatment of alcoholics near St. Petersburg.

The patients in this hospital are all voluntary. The psychotherapy is usually limited to the area of alcohol

abuse, and the goal of treatment is overcoming their so-called “alcohol denial.”

A typical patient in our ketamine program stays in the hospital about one month. During the first phase of

therapy, we treat their alcohol withdrawal syndrome and any related anxiety or affective disorders. Then,

we start rational, cognitive psychotherapy in order to establish a mental set of sobriety and a negative

attitude toward alcohol. However, we go beyond the problem of alcohol abuse to explore broader issues

including the patient’s life history, relationships, and world view.

Later in the program, we tell them that they will undergo a new treatment which will allow them to see

and feel the subconscious roots of their problems. We help our patients understand that their alcohol

problem is only a superficial symptom – the manifestation of more deeply rooted problems.

On the day of the session, we give the patient an intragluteal injection of about 150 mg. of ketamine

(approx. 2 mg. per kg.). We prefer the intramuscular route because the effect is more gradual, and the

transpersonal state lasts longer. With an intravenous injection, the effect lasts only about fifteen to twenty

minutes, but after an intramuscular injection, it lasts from about forty-five minutes to an hour.

We tell the patient that they will enter some unusual states of consciousness and that they may feel

detached from their body. We also instruct them to surrender fully to the experience. I gave up our original

approach of trying to induce something specific in the patient during the session. Under the influence of

ketamine, especially in these doses, one has no direct contact with ordinary reality. The psychotherapist

can try to influence the experience, but it will be in vain. We are available, however, to give emotional

support if the patient requests it.

As with other psychedelics, music also enhances the ketamine experience. We have found composers

whose music is particularly conducive for ketamine sessions, such as Jean Michael Jarre or Kitaro. After

forty-five minutes to an hour, the patient slowly comes back from the experience. During the recovery

period, which takes about an hour and a half or two hours, the patient begins to feel ordinary reality

returning, but part of their consciousness is still in another world, another dimension. At this point in the

session, the patient usually begins to describe their experience, and we begin some interpretation. After

the session, the patient goes to rest, and we ask them to write down a detailed report of their experience

that evening. The next day, we have a follow-up session which includes an in-depth discussion of their

experience. When several patients have ketamine sessions on the same day, we do it as group therapy. We

gather these patients in a group the day before treatment and the day after, because when they all share the

experience, it is usually more powerful.

Regarding spiritual experiences induced by ketamine, it is interesting that many people who never thought

about spirituality or the meaning of life reported having experiences that one might read about only in

spiritual texts or Eastern teachings. At the beginning of ketamine sessions, people often experience the

separation of consciousness from the body and the dissolving of the body ego. For many patients, it is a

profound insight that they can exist without their bodies as pure consciousness or pure spirit. Many of

them said that as a result of their experience, they understood the Christian notion of the separation of the

soul and the body, and that they now believe some part of them will continue to exist after death. There

were several cases where people reported contact with God, but this is usually not an anthropomorphic

figure. They describe an ocean of brilliant white light, sometimes a golden white light, which is filled with

love, bliss and energy. After coming back to ordinary consciousness, they feel sure that they have had

contact with a higher power. There were also several cases where people saw Jesus Christ approaching

them. It seems ironic that so many of our patients, through their own experience, were converted to a

more spiritual approach to life, despite living in a country where people have been brought up for

generations with atheism.

A second observation is that many patients report the existence of other dimensions or other worlds that

are parallel to ours. They usually report that these other dimensions seem as real or more real than our

own. Some patients experience this “ego death”, or the dissolving of the individual sense of self, which 1

had experienced. Of course they do not use these terms. They might say, “I ceased to exist, I disappeared,

yet still something existed. It was like I became the whole universe or the whole cosmos”. In my

experience, I also got the feeling of the collapse of space and time, and I really felt that space and time

were illusions. It was as if I had collapsed into a single point with no space and no time, and it was from

this point that the whole universe seemed to be manifesting.

Another interesting observation, although not a topic of our research, is the correlation between the type

of personality and the type of experience under the influence of ketamine. People who are very controlled

and have difficulties letting go, or who have problems with relationships, often have negative experiences

with ketamine. For them, the dissolving of the individual sense of self is horrible. For other patients who

are more relaxed and able to surrender, who have a deep capacity to love, the experience is usually

blissful, even ecstatic.

The action of ketamine is somewhat unique in comparison with other psychoactive substances. Stanislav

Grof has divided the psychedelic experience and other experiences of altered states of consciousness into

three main categories; the psychodynamic level, where people recall the past events of their lives,

especially childhood memories; the perinatal level, or the recollection of the birth experience; and the

transpersonal level, which includes the mystical experience. “Transpersonal” refers to experiences which

go beyond one’s individual personality and involve the transcendence of the spatial or temporal

boundaries of ordinary consciousness. One might also experience mythological themes or archetypal

figures like the god or goddess, or the expansion of consciousness to encompass the whole cosmos, etc.

Ketamine differs from other psychedelics in that in medium doses, it usually it does not engage the

psychodynamic level. Instead, it almost “throws” one into the transpersonal realm. The other major

psychedelics, such as LSD or mescaline, are more gradual and gentle, and in medium doses they usually

engage the psychodynamic level. To induce transpersonal states, higher doses of these substances are

normally required.

Of course, the effects of ketamine are also a function of dosage. In low doses, one remains in contact with

ordinary reality, but with eyes closed one can see some strange images. They are not human forms, but

usually geometric shapes like spheres or triangles, or simply open spaces.

Following treatment, the patient is released from the hospital. Every two or three months, we see them for

follow-up visits. We have collected data on patients who have undergone ketamine-assisted

psychotherapy after spending one month in the hospital. About sixty eight per cent of these patients

remain sober for one year following treatment. This is a very high success rate in comparison with other

programs for alcoholism. In the control group, which was composed of patients who were in the same

hospital, who were the same average age, and who were in the same stage of the development of

alcoholism, the percentage who remained sober for one year was about forty-five to fifty per cent. So we

have proven statistically that the ketamine experience is very useful. We believe that these positive results

in maintaining sobriety were not achieved simply because we were more successful in establishing a set

of sobriety and a deeper negative attitude toward alcohol, but rather because of changes in the values,

relationships, and world view of these patients. They began to see other goals, other values, other

pleasures in their lives, and this was the main reason for their sobriety. For us, this was much more

interesting than the limited issue of keeping sober.

We also administered several psychological tests before and after the ketamine treatment. We gave

patients the MMPI, and after the session the scales which indicated anxiety and depression decreased

statistically, even though these patients were not primarily neurotic or depressive. The same results were

also confirmed by the Zung anxiety and depression scales, but we were interested in more than these

clinical symptoms. We also tried to measure changes in values and world view after treatment. It was

difficult to find an instrument to measure these changes, but the two scales we found most useful were the

Omega Life Changes Questionnaire by Kenneth Ring, and the Self-Assessment Spirituality Scale by

Charles Whitfield. Kenneth Ring is a professor of psychology at the University of Connecticut who has

done extensive research on near-death experiences, and he created The Life Changes Questionnaire. It

consists of some thirty questions that assess the individual’s values, goals, and attitudes toward material

things, etc. Our patients showed the most significant changes in exactly this scale. According to the results

of this questionnaire, they shifted to a more spiritual world view. We also used the Self-Assessment

Spirituality Scale by Charles Whitfield, an American researcher who has tried to introduce spirituality into

recovery from alcoholism. In addition, we developed our own instrument, called the “repertory grid”,

which measures psychosemantic fields. It measures the meanings of key words such as life, love, death,

despair, Jesus Christ, etc. Through this tool, we can measure changes in the patient’s attitude toward

various aspects of life. This scale also showed that our patients shifted to a wider, more spiritual world

view.

Our anecdotal observations also confirmed these changes. Some patients began to write poems after their

ketamine sessions, while others began to paint. Many of them began to feel more connected with nature

and reported, for example, that after treatment they went to the countryside more often. When some

patients went back to their families, they noticed problems in their relationships, or certain idiosyncrasies

of their spouses and relatives which they were unaware of before treatment. Ketamine seems to increase

the capacity for detached observation.

I would also like to relate some unusual anecdotes connected with our research. About one year after we

began our study, a group composed of two men and one woman appeared at our hospital who were very

strange looking, wore strange clothes, and had strange, shiny eyes that seemed out of focus. They called

themselves “magicians”, and said that they sensed in their meditations and magic practice that in this

hospital, some people were throwing other souls into the “astral plane”. They had come to see what we

were doing, like “astral police”. Prior to this, we had not published the results of our work, and only a few

professionals knew about it. Also, this hospital is situated in the suburbs of St. Petersburg, and is not

widely known. So we described our work and showed them our hospital. They approved! They also told

us that they themselves used ketamine for their underground magic practice. As far as I understood from

our conversations, their practice to some extent imitates or closely parallels the practice of Carlos

Casteneda. They had gone into the forest and found power spots and power plants, and practiced

meditation there. This acquaintance was useful for us because, as it turned out, they had a tremendous

volume of underground psychedelic literature, translated into Russian. When we shifted to the

transpersonal paradigm, we began a literature search, and we sent requests to several libraries, including

the main state library in Moscow. Although they probably had this literature, it was two or three years

ago, before the changes in Russia, and they didn’t send it to us. So the magicians gave us, for example,

Peter Stafford’s Psychedelics Encyclopedia. Later, there was another interesting episode with these

magicians. One of the men told me that they also used mushrooms growing in the forest near the region of

St. Petersburg to induce psychedelic states. At first I didn’t believe him, but he gave me a dried specimen,

and I identified it in the Psychedelics Encyclopedia as Psilocybe semilanceata.

To date, the total number of patients treated with this method is about four hundred. Our results show that

ketamine-assisted psychotherapy is significantly more effective in treating alcoholism than standard nondrug

psychotherapy. In addition, ketamine-assisted psychotherapy results in positive life changes which

go beyond the limited goal of maintaining sobriety, including profound changes in values, relationships,

and world view. In the near future, we plan to continue our work with alcoholic patients and to develop

this approach further with neurotic patients using repeated ketamine sessions.

Note: The author would like to thank Robert Zanger and Blackbird Willow for their assistance in the preparation of this article.

Reprinted from the Fall 1991 issue of the Albert Hofmann Foundation bulletin.

https://journals.sagepub.com/doi/10.1177/0269881120970879

Abstract

Abstract

Read entire study on sciencedirect.com

Abstract

Introduction: Esketamine nasal spray received approval for treatment-resistant depression in March 2019. Objective: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019–March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals. Methods: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests. Results: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ² = 125.29, p < 0.001, χ² = 9.08, p = 0.003, χ² = 8.14, p = 0.004, χ² = 19.48, p < 0.001, χ² = 25.62, p < 0.001, and χ² = 16.79, p < 0.001, respectively). Conclusions: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.

© 2020 S. Karger AG, Basel

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Abstract

The objective of this study was to investigate the safety of repeated parenteral ketamine for depression. An electronic survey inquiring about the frequency of adverse events was distributed to providers of parenteral ketamine for depression. In addition, the investigators conducted a search of published studies describing six or more repeated parenteral ketamine treatments administered to individuals for depression, and extracted reported adverse events. The survey was sent to 69 providers, of which 36 responded (52% response rate); after eliminating those that were incomplete, 27 were included in the analysis. The providers in the analysis collectively reported treating 6630 patients with parenteral ketamine for depression, one-third of whom received more than 10 treatments. Only 0.7% of patients experienced an adverse eect that required discontinuation of ketamine. Psychological distress during the treatment was the most frequent cause. Other adverse events were extremely rare (such as bladder dysfunction (0.1%), cognitive decline (0.03%) and psychotic symptoms (0.03%)). Among the 20 published reports of repeated parenteral ketamine treatments, rates of significant adverse events resulting in discontinuation were low (1.2%). The rate of adverse eects reported in the survey and the published literature is low, and suggests that long-term treatment of depression with ketamine is reasonably safe.

Keywords: ketamine; major depressive disorder; depression; addiction

Pdf of the full study

Abstract

Major depressive disorder (MDD) is a common mental health disorder that brings severe disease burden worldwide. Traditional antidepressants are mainly targeted at monoamine neurotransmitters, with low remission rates and high recurrence rates. Ketamine is a noncompetitive glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, and its rapid and powerful antidepressant effects have come to light. Its antidepressant mechanism is still unclarified. Research found that ketamine had not only antagonistic effect on NMDAR but also strong immunomodulatory effect, both of which were closely related to the pathophysiology of MDD. Although there are many related studies, they are relatively heterogeneous. Therefore, this review mainly describes the immune mechanisms involved in MDD and how ketamine plays an antidepressant role by regulating peripheral and central immune system, including peripheral inflammatory cytokines, central microglia, and astrocytes. This review summarizes the related research, finds out the deficiencies of current research, and provides ideas for future research and the development of novel antidepressants.

Read the entire study here: https://www.degruyter.com/document/doi/10.1515/tnsci-2020-0167/html

Abstract

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Abstract

© 2022 Pharmacotherapy Publications, Inc.

Complete Study: 

https://pubmed.ncbi.nlm.nih.gov/35122282/

Abstract

Complete Study: 

https://onlinelibrary.wiley.com/doi/full/10.1002/ejp.1914?casa_token=nnUX13IGqIgAAAAA%3AHyzcBeqhLuqas16n4FVp1i3nbVYQZoOM3vWbTC5TpDDC4nuH4UF3wTHJfSMRQ2W2nCUf5Qt0wzJscPUhttps://pubmed.ncbi.nlm.nih.gov/35122282/